Phenoxybenzylamine derivatives as SSRls

ABSTRACT

A compound of general formula (I) wherein R 1  and R 2  are H, C 1 -C 6 alkyl or (CH 2 ) d (C 3 -C 6 cycloalkyl) wherein d=0, 1, 2 or 3; or R 1  and R 2  together with the nitrogen to which they are attached form an azetidine ring; Z or Y is —SR 3  and the other Z or Y is halogen or —R 3 ; wherein R 3  is C 1 -C 4  alkyl optionally substituted with fluorine; except that R 3  is not CF 3 ; or Z and Y are linked so that, together with the interconnecting atoms, Z and Y form a fused 5 to 7-membered carbocyclic or heterocyclic ring, and wherein when Z and Y form a heterocyclic ring, in addition to carbon atoms, the linkage contains one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; R 4  and R 5 , which may be the same or different, are: A—X, wherein A═—CH═CH— or —(CH 2 ) p — where p is 0, 1 or 2; X is hydrogen, F, Cl, Br, I, CONR 6 R 7 , SO 2 NR 6 R 7 , SO 2 NHC(═O)R 6 , OH, C 1-4 alkoxy, NR 8 SO 2 R 9 , NO 2 , NR 6 R 11 , CN, CO 2 R 10 , CHO, SR 10 , S(O)R 9  or SO 2 R 10 ; or a 5- or 6-membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from N, S and O, optionally substituted independently by one or more R 13 ; wherein R 13  is hydroxy, C 1 -C 4 alkoxy, F, C 1 -C 6 alkyl, haloalkyl, haloalkoxy, —NH 2 , —NH(C 1 -C 6 alkyl) or —N(C 1 -C 6 alkyl) 2 .

[0001] This invention relates to novel diphenyl ether compounds whichinhibit monoamine re-uptake. In particular compounds of the presentinvention exhibit activity as selective serotonin re-uptake inhibitors(SSRIs) and have utility therefore in a variety of therapeutic areas.Notably the compounds of the present invention are useful in thetreatment or prevention of a variety of disorders, including those inwhich the regulation of monoamine transporter function is implicated,such as depression, attention deficit hyperactivity disorder,obsessive-compulsive disorder, post-traumatic stress disorder, substanceabuse disorders and sexual dysfunction including premature ejaculation,and to pharmaceutical formulations containing such compounds.

[0002] According to a first aspect, the invention provides a compound ofgeneral formula (I), pharmaceutically acceptable salts, solvates orpolymorphs thereof;

[0003] wherein;

[0004] R¹ and R², which may be the same or different, are H, C₁-C₆alkylor (CH₂)_(d)(C₃-C₆cycloalkyl) wherein d=0, 1, 2 or 3; or R¹ and R²together with the nitrogen to which they are attached form an azetidinering;

[0005] Z or Y is —SR³ and the other Z or Y is halogen or —R³; wherein R³is independently C₁-C₄ alkyl optionally substituted with fluorine;except that R³ is not CF₃;

[0006] or Z and Y are linked so that, together with the interconnectingatoms, Z and Y form a fused 5 to 7-membered carbocyclic or heterocyclicring which may be saturated, unsaturated or aromatic, and wherein when Zand Y form a heterocyclic ring, in addition to carbon atoms, the linkagecontains one or two heteroatoms independently selected from oxygen,sulfur and nitrogen; with the proviso that when R⁵ is fluorine and R² ismethyl then the fused ring is not 1,3-dioxolane and Z and Y together donot form a fused phenyl ring;

[0007] R⁴ and R⁵, which may be the same or different, are:

[0008] A—X, wherein A═—CH═CH— or —(CH₂)_(p)— where p is 0, 1 or 2; X ishydrogen, F, Cl, Br, I, CONR⁶R⁷, SO₂NR⁶R⁷, SO₂NHC(═O)R⁶, OH, C₁₋₄alkoxy,NR⁸SO₂R⁹, NO₂, NR⁶R¹¹, CN, CO₂R¹⁰, CHO, SR¹⁰, S(O)R⁹ or SO₂R¹⁰; R⁶, R⁷,R⁸ and R¹⁰ which may be the same or different, are hydrogen or C₁₋₆alkyloptionally substituted independently by one or more R¹²; R⁹ is C₁₋₆alkyl optionally substituted independently by one or more R¹²; R¹¹ ishydrogen, C₁₋₆ alkyl optionally substituted independently by one or moreR¹², C(O)R⁶, CO₂R⁹, C(O)NHR⁶ or SO₂NR⁶R⁷; R¹² is F (preferably up to 3),OH, CO₂H, C₃₋₆cycloalkyl, NH₂, CONH₂, C₁₋₆alkoxy, C₁₋₆alkoxycarbonyl ora 5- or 6-membered heterocyclic ring containing 1, 2 or 3 heteroatomsselected from N, S and O optionally substituted independently by one ormore R¹³; or R⁶ and R⁷, together with the nitrogen to which they areattached, form a 4-, 5- or 6-membered heterocyclic ring optionallysubstituted independently by one or more R¹³; or

[0009] a 5- or 6-membered heterocyclic ring containing 1, 2 or 3heteroatoms selected from N, S and O optionally substitutedindependently by one or more R¹³; wherein R¹³ is hydroxy, C₁-C₄alkoxy,F, C₁-C₆alkyl, haloalkyl, haloalkoxy, —NH₂, —NH(C₁-C₆alkyl) or—N(C₁-C₆alkyl)₂.

[0010] Unless otherwise indicated, any alkyl group may be straight orbranched and is of 1 to 6 carbon atoms, preferably 1 to 4 andparticularly 1 to 3 carbon atoms.

[0011] Unless otherwise indicated, any carbocyclyl group contains 3 to 8ring-atoms, and may be saturated, unsaturated or aromatic. Preferredsaturated carbocyclyl groups are cyclopropyl, cyclopentyl or cyclohexyl.Preferred unsaturated carbocyclyl groups contain up to 3 double bonds. Apreferred aromatic carbocyclyl group is phenyl. The term carbocylicshould be similarly construed. In addition, the term carbocyclylincludes any fused combination of carbocyclyl groups, for examplenaphthyl, phenanthryl, indanyl and indenyl.

[0012] Unless otherwise indicated, any heterocyclyl group contains 5 to7 ring-atoms up to 4 of which may be hetero-atoms such as nitrogen,oxygen and sulfur, and may be saturated, unsaturated or aromatic.Examples of heterocyclyl groups are furyl, thienyl, pyrrolyl,pyrrolinyl, pyrrolidinyl, imidazolyl, dioxolanyl, oxazolyl, thiazolyl,imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl,pyrazolidinyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl,thiadiazolyl, pyranyl, pyridyl, piperidinyl, dioxanyl, morpholino,dithianyl, thiomorpholino, pyridazinyl, pyrimidinyl, pyrazinyl,piperazinyl, sulfolanyl, tetrazolyl, triazinyl, azepinyl, oxazepinyl,thiazepinyl, diazepinyl and thiazolinyl. In addition, the termheterocyclyl includes fused heterocyclyl groups, for examplebenzimidazolyl, benzoxazolyl, imidazopyridinyl, benzoxazinyl,benzothiazinyl, oxazolopyridinyl, benzofuranyl, quinolinyl,quinazolinyl, quinoxalinyl, dihydroquinazolinyl, benzothiazolyl,phthalimido, benzofuranyl, benzodiazepinyl, indolyl and isoindolyl. Theterm heterocyclic should be similarly construed.

[0013] Halo means fluoro, chloro, bromo or iodo.

[0014] Preferably R¹ and R², which may be the same or different, arehydrogen or C₁-C₆alkyl. More preferably hydrogen or methyl.

[0015] When Z or Y is —SR³, R³ is preferably methyl or ethyl.

[0016] When Z and Y form a fused ring, the ring is preferably aheterocyclic ring. More preferably, the linkage contains one or twosulfur atoms.

[0017] Preferably R⁴ and R⁵ are not both hydrogen.

[0018] Preferably R⁴ and R⁵, which may be the same or different, are

[0019] —(CH₂)_(p)—X, where p is 0, 1 or 2 (preferably 0 or 1); X ishydrogen, hydroxy, CONR⁶R⁷, SO₂NR⁶R⁷, NR⁸SO₂R⁹, SR¹⁰, SOR⁹ or SO₂R¹⁰wherein R⁶, R⁷, R⁸, R⁹ and R¹⁰ are as defined in the first aspect, or

[0020] a 5- or 6-membered heterocyclic ring containing 1, 2 or 3heteroatoms selected from N, S and O (preferably oxadiazolyl, triazolyl,imidazolyl, oxazolyl, pyrazolyl, pyridinyl or pyrimidinyl).

[0021] More preferably R⁴ and R⁵, which may be the same or different,are:

[0022] —(CH₂)_(p)—X, where p is 0 or 1; X is hydrogen, hydroxy, CONR⁶R⁷,SO₂NR⁶R⁷ or NR⁸SO₂R⁹; wherein R⁶ and R⁷, which may be the same ordifferent, are hydrogen or C₁-C₃alkyl optionally substituted by hydroxy,—CONH₂ or C₁-C₃alkoxy (preferably methoxy); R⁸ is hydrogen, hydroxyethylor methyl; or R⁹ is methyl, ethyl, isopropyl, trifluoromethyl ormethoxyethyl; or

[0023] triazolyl, imidazolyl or pyrazolyl.

[0024] More preferably still R⁴ is hydrogen.

[0025] Preferably R⁶ and R⁷, which may be the same or different, arehydrogen, C₁-C₃alkyl optionally substituted by hydroxy, —CONH₂ orC₁-C₃alkoxy (preferably methoxy). More preferably R⁶ and R⁷, which maybe the same or different, are hydrogen or methyl, more preferably stillhydrogen.

[0026] When present, R¹² is preferably oxadiazolyl, triazolyl,imidazolyl, oxazolyl, pyrazolyl, pyridinyl or pyrimidinyl. Morepreferably triazolyl, imidazolyl or pyrazolyl.

[0027] In the case where R⁶ and R⁷, together with the nitrogen to whichthey are attached, form a heterocyclic ring, preferred rings arepyrrolidine or piperidine rings each of which may be substituted by OHor CONH₂ or a morpholine ring which may be substituted by CONH₂.

[0028] Preferably R¹¹ is hydrogen or C₁₋₆ alkyl.

[0029] Preferably R⁸ is hydrogen, hydroxyethyl or methyl. Morepreferably hydrogen.

[0030] Preferably R⁹ is methyl, ethyl, isopropyl, trifluoromethyl ormethoxyethyl. More preferably methyl or ethyl (preferably methyl).

[0031] Preferably R¹⁰ is methyl or ethyl.

[0032] Preferably p is 1 or 0, more preferably 0.

[0033] Preferably

[0034] R¹ and R², which may be the same or different, are hydrogen ormethyl;

[0035] when present, R³ is methyl or ethyl; or Z and Y are linked sothat, together with the interconnecting atoms, Z and Y form a fused 5 to7-membered carbocyclic or heterocyclic ring which may be saturated,unsaturated or aromatic, and wherein when Z and Y form a heterocyclicring, in addition to carbon atoms, the linkage contains one or twoheteroatoms independently selected from oxygen, sulfur and nitrogen; and

[0036] R⁴ and R⁵, which may be the same or different, are

[0037] (CH₂)_(p)—X, where p is 0 or 1; X is hydrogen, hydroxy, CONR⁶R⁷,SO₂NR⁶R⁷, NR⁸SO₂R⁹, SR¹⁰, SOR⁹ or SO₂R¹⁰ and wherein R⁶ and R⁷, whichmay be the same or different, are hydrogen, C₁-C₃alkyl optionallysubstituted by hydroxy, —CONH₂ or C₁-C₃alkoxy (preferably methoxy); orR⁶ and R⁷, together with the nitrogen to which they are attached, mayform a morpholine, pyrrolidine or piperidine ring each of which may besubstituted by OH or CONH₂; R⁸ is hydrogen, hydroxyethyl or methyl(preferably hydrogen); R⁹ is methyl, ethyl, isopropyl, trifluoromethylor methoxyethyl; and R¹⁰ is methyl or ethyl; or

[0038] an oxadiazolyl, triazolyl, imidazolyl, oxazolyl, pyrazolyl,pyridinyl or pyrimidinyl group.

[0039] More preferably

[0040] R¹ and R², which may be the same or different, are hydrogen ormethyl;

[0041] when present, R³ is methyl or ethyl; or Z and Y are linked sothat, together with the interconnecting atoms, Z and Y form a fused 5 to7-membered heterocyclic ring containing 1 or 2 sulfur atoms; and

[0042] R⁴ and R⁵, which may be the same or different, are

[0043] —(CH₂)_(p)—X, where p is 0 or 1; X is hydrogen, hydroxy, CONR⁶R⁷,SO₂NR⁶R⁷ or NR⁸SO₂R⁹; wherein R⁶ and R⁷, which may be the same ordifferent, are hydrogen, C₁-C₃alkyl optionally substituted by hydroxy,—CONH₂ or C₁-C₃alkoxy (preferably methoxy); R⁸ is hydrogen, hydroxyethylor methyl; R⁹ is methyl, ethyl, isopropyl, trifluoromethyl ormethoxyethyl; or

[0044] triazolyl, imidazolyl or pyrazolyl.

[0045] More preferably still

[0046] R¹ and R², which may be the same or different, are hydrogen ormethyl;

[0047] when present R³is methyl or ethyl; or Z and Y are linked so that,together with the interconnecting atoms, Z and Y form a fused saturated5 to 7-membered heterocyclic ring containing 1 or 2 sulfur atoms;

[0048] R⁴ is hydrogen, and

[0049] R⁵ is

[0050] —(CH₂)_(p)—X, where p is 0 or 1; X is hydrogen, hydroxy, CONR⁶R⁷,SO₂NR⁶R⁷ or NR⁸SO₂R⁹; wherein R⁶ and R⁷, which may be the same ordifferent, are hydrogen, C₁-C₃alkyl optionally substituted by hydroxy,—CONH₂ or C₁-C₃alkoxy (preferably methoxy); R⁸ is hydrogen, hydroxyethylor methyl; R⁹ is methyl, ethyl, isopropyl, trifluoromethyl ormethoxyethyl; or

[0051] triazolyl, imidazolyl or pyrazolyl.

[0052] More preferably still R⁴ and R⁵ are not both hydrogen.

[0053] Preferred compounds are:

[0054]4-(2,3-dihydro-1-benzothien-5-yloxy)-3-[(methylamino)methyl]-benzenesulfonamide(Example 2);

[0055]3-[(dimethylamino)methyl]-4-[3-methyl-4-(methylsulfanyl)phenoxy]-benzenesulfonamide(Example 12);

[0056]4-(2,3-dihydro-1-benzothien-5-yloxy)-3-[(dimethylamino)methyl]-benzenesulfonamide(Example 16);

[0057]4-[3-chloro-4-(methylsulfanyl)phenoxy]-3-[(dimethylamino)methyl]-benzenesulfonamide(Example 17);

[0058]3-[(dimethylamino)methyl]-4-[3-fluoro-4-(methylsulfanyl)phenoxy]-benzenesulfonamide(Example 18);

[0059] N,N-dimethyl-N-[2-(6-quinolinyloxy)benzyl]amine (Example 29);

[0060] 3-[(methylamino)methyl]-4-(6-quinolinyloxy)benzenesulfonamide(Example 35);

[0061]4-(2,3-dihydro-1-benzothien-5-yloxy)-3-[(methylamino)methyl]benzamide(Example 60);

[0062]4-(2,3-dihydro-1-benzothien-5-yloxy)-N-methyl-3-[(methylamino)methyl]-benzamide(Example 62);

[0063]N-{3-[(methylamino)methyl]-4-[3-methyl-4-(methylsulfanyl)phenoxy]benzyl}methanesulfonamide(Example 75);

[0064]3-[(methylamino)methyl]-4-[3-methyl-4-(methylsulfanyl)phenoxy]benzamide(Example 79);

[0065]4-(2,3-dihydro-1,4-benzoxathiin-7-yloxy)-3-[(dimethylamino)methyl]benzamide(Example 88);

[0066]{3-[(dimethylamino)methyl]-4-[3-fluoro-4-(methylsulfanyl)phenoxy]phenyl}-methanol(Example 90);

[0067] 3-[(dimethylamino)methyl]-4-(6-quinolinyloxy)benzamide (Example100);

[0068] 3-[(methylamino)methyl]-4-(6-quinolinyloxy)benzamide (Example102);

[0069]N-methyl-N-{3-[(methylamino)methyl]-4-[3-methyl-4-(methylsulfanyl)phenoxy]-phenyl}methanesulfonamide(Example 116) and

[0070]N-{4-(2,3-dihydro-1,4-benzoxathiin-7-yloxy)-3-[(dimethylamino)methyl]phenyl}-methanesulfonamide(Example 124).

[0071] According to a second aspect the invention provides compound offormula (I) or (XIX)

[0072] and pharmaceutically acceptable salts or solvates thereof wherein(in this aspect): R¹ and R² independently represent H, C₁-C₆ alkyl or(CH₂)_(d)(C₃-C₆cycloalkyl) wherein d=0, 1, 2 or 3, or wherein NR¹R² whentaken together represent a 4-membered ring wherein R¹ and R² togetherrepresent C₃ alkyl; Z and Y both independently represent —SR³ wherein,when Z═—SR³ then Y=halogen, —OR^(a), —R^(a) or —SR^(a); or when Y═—SR³then Z=halogen, —OR^(a), R^(a) or —SR^(a); and R³ and R^(a)independently represent: C₁-C₄ alkyl (optionally substituted withfluorine atoms e.g. —CF₃); or Z and Y when taken together can representa fused 5 to 7 membered ring as illustrated by general formula XIX,wherein said 5 to 7 membered ring may be saturated, unsaturated oraromatic, and wherein said 5 to 7 membered ring may optionally containone or more heteroatoms P and Q, wherein P and Q=may be independently O,S or N, and wherein E, F, or G independently represent CH or CH₂ andwherein k and p may independently be=0, 1, 2 or 3, and m=1, 2 or 3; and

[0073] R⁴ and R⁵ independently represent A—X wherein A═—(CH₂)_(n)—,wherein n represents 0, 1 or 2 and wherein X represents: H, F, Cl, Br,I, CONR⁶R⁷ or SO₂NR⁶R⁷, OH, NR⁸SO₂R⁹, NO₂, NR⁶R¹¹, CN, CO₂R¹⁰, CHO,S(O)_(m)R¹⁰ wherein m=0, 1 or 2 and wherein R⁶, R⁷, R⁸ and R¹⁰independently represent H or C₁₋₆ alkyl, wherein R⁹ represents C₁₋₆alkyl, R¹¹ represents H, C₁₋₆ alkyl, C(O)R⁶, CO₂R⁹, C(O)NHR⁶ or SO₂NR⁶R⁶and wherein said C₁₋₆ alkyl group is optionally substituted by one ormore groups selected from OH, CO₂H, C₃₋₆ cycloalkyl, NH₂, CONH₂, C₁₋₆alkoxy, C₁₋₆ alkoxycarbonyl and a 5- or 6-membered heterocyclic ringcontaining 1, 2 or 3 heteroatoms selected from N, S and O; or with theproviso that when P═Q=oxygen then both k and p are not zero; with theproviso that Z and Y together do not form a fused phenyl ring; R⁴ or R⁵may be representative of a 5- or 6-membered heterocyclic ring containing1, 2 or 3 heteroatoms selected from N, S and O; and in addition, R⁶ andR⁷ may, together with the N atom to which they are attached, represent a5- or 6- membered heterocyclic ring which may be optionally substituted;and pharmaceutically acceptable salts or solvates thereof with theproviso that both R⁴ and R⁵ are not H.

[0074] For the avoidance of doubt, unless otherwise indicated, the termsubstituted means substituted by one or more defined groups. In the casewhere groups may be selected from a number of alternatives groups, theselected groups may be the same or different.

[0075] For the avoidance of doubt, the term independently means thatwhere more than one substituent is selected from a number of possiblesubstituents, those substituents may be the same or different.

[0076] According to a third aspect, the invention provides a compound ofgeneral formula I and pharmaceutically acceptable salts thereof, whereinR¹, R², R³, Z and Y are as defined in the first aspect; and R⁴ and R⁵,which may be the same or different, are —(CH₂)_(p)—A′, wherein p is 0, 1or 2 and A′ is a polar group. In this aspect, polar groups may bedefined as those having a negative π-value (see C Hansch and A Leo,‘Substituent Constants for Correlation Analysis in Chemistry andBiology’, Wiley, N.Y., 1979). In this system, H has a π-value of 0.00,—OCH₃ has a π-value of −0.02, and —SO₂NH₂ has a π-value of −1.82, forexample [see Table VI-I, ‘Well-Characterized Aromatic Substituents’, p49, ibid]. More preferred polar groups have a more negative π-value:thus, preferred groups have π-values of a greater negative value than−0.1, more preferably a greater negative value than −0.5, and mostpreferably a greater negative value than −1.0. Even when p is other thanzero in the above definition, the definition of A′ is based on the abovereference as if p was zero.

[0077] Unless otherwise specified, the compounds of the first, secondand third aspects are hereinafter defined as compounds of the invention.

[0078] The compounds of the invention have the advantage that they areselective inhibitors of the re-uptake of serotonin (SRIs) (and so arelikely to have reduced side effects), they have a rapid onset of action(making them suitable for administration shortly before an effect isrequired), they have desirable potency and associated properties.Compounds that selectively inhibit the re-uptake of serotonin, but notnoradrenaline or dopamine, are preferred.

[0079] We have found that compounds of formula I which possess theseproperties have a relatively polar group at R⁴/R⁵.

[0080] The pharmaceutically or veterinarily acceptable salts of thecompounds of formula I which contain a basic centre are, for example,non-toxic acid addition salts formed with inorganic acids such ashydrochloric, hydrobromic, hydroiodic, sulfuric and phosphoric acid,with carboxylic acids or with organo-sulfonic acids. Examples includethe HCl, HBr, HI, sulfate or bisulfate, nitrate, phosphate or hydrogenphosphate, acetate, benzoate, succinate, saccharate, fumarate, maleate,lactate, citrate, tartrate, gluconate, camsylate, methanesulfonate,ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate salts.Compounds of the invention can also provide pharmaceutically orveterinarily acceptable metal salts, in particular non-toxic alkali andalkaline earth metal salts, with bases. Examples include the sodium,potassium, aluminium, calcium, magnesium, zinc, diolamine, olamine,ethylenediamine, tromethamine, chloine, megulamine and diethanolaminesalts. For reviews on suitable pharmaceutical salts see Berge et al, J.Pharm, Sci., 66, 1-19, 1977; P L Gould, International Journal ofPharmaceutics, 33 (1986), 201-217; and Bighley et al, Encyclopedia ofPharmaceutical Technology, Marcel Dekker Inc, New York 1996, Volume 13,page 453-497.

[0081] Hereinafter, the compounds, their pharmaceutically acceptablesalts, their solvates and polymorphs, defined in any aspect of theinvention (except intermediate compounds in chemical processes) arereferred to as “compounds of the invention”.

[0082] The pharmaceutically acceptable solvates of the compounds of theinvention include the hydrates thereof.

[0083] The compounds of the invention may possess one or more chiralcentres and so exist in a number of stereoisomeric forms. Allstereoisomers and mixtures thereof are included in the scope of thepresent invention. Racemic compounds may either be separated usingpreparative HPLC and a column with a chiral stationary phase or resolvedto yield individual enantiomers utilising methods known to those skilledin the art. In addition, chiral intermediate compounds may be resolvedand used to prepare chiral compounds of the invention.

[0084] In cases where the compounds of the invention exist as the E andZ isomers, the invention includes individual isomers as well as mixturesthereof.

[0085] In cases where compounds of the invention exist as tautomericisomers, the invention includes individual tautomers as well as mixturesthereof.

[0086] In cases where the compounds of the invention exist as opticalisomers, the invention includes individual isomers as well as mixturesthereof.

[0087] In cases where the compounds of the invention exist asdiastereoisomers, the invention includes individual diastereoisomers aswell as mixtures thereof.

[0088] Separation of diastereoisomers or E and Z isomers may be achievedby conventional techniques, e.g. by fractional crystallisation,chromatography or H.P.L.C. An individual enantiomer of a compound of theinvention may be prepared from a corresponding optically pureintermediate or by resolution, such as by H.P.L.C. of the correspondingracemate using a suitable chiral support or by fractionalcrystallisation of the diastereoisomeric salts formed by reaction of thecorresponding racemate with a suitable optically active acid or base, asappropriate.

[0089] The compounds of the invention may exist in one or moretautomeric forms. All tautomers and mixtures thereof are included in thescope of the present invention. For example, a claim to2-hydroxypyridinyl would also cover its tautomeric form, α-pyridonyl.

[0090] It will be appreciated by those skilled in the art that certainprotected derivatives of compounds of the invention, which may be madeprior to a final deprotection stage, may not possess pharmacologicalactivity as such, but may, in certain instances, be administered orallyor parenterally and thereafter metabolised in the body to form compoundsof the invention which are pharmacologically active. Such derivativesmay therefore be described as “prodrugs”. Further, certain compounds ofthe invention may act as prodrugs of other compounds of the invention.

[0091] All protected derivatives and prodrugs of compounds of theinvention are included within the scope of the invention. Examples ofsuitable pro-drugs for the compounds of the present invention aredescribed in Drugs of Today, Volume 19, Number 9, 1983, pp 499-538 andin Topics in Chemistry, Chapter 31, pp 306-316 and in “Design ofProdrugs” by H. Bundgaard, Elsevier, 1985, Chapter 1 (the disclosures inwhich documents are incorporated herein by reference).

[0092] It will further be appreciated by those skilled in the art, thatcertain moieties, known to those skilled in the art as “pro-moieties”,for example as described by H. Bundgaard in “Design of Prodrugs” (thedisclosure in which document is incorporated herein by reference) may beplaced on appropriate functionalities when such functionalities arepresent within the compounds of the invention.

[0093] Preferred prodrugs for compounds of the invention include:esters, carbonate esters, hemi-esters, phosphate esters, nitro esters,sulfate esters, sulfoxides, amides, carbamates, azo-compounds,phosphamides, glycosides, ethers, acetals and ketals.

[0094] The invention also includes all suitable isotopic variations ofthe compounds of the invention. An isotopic variation is defined as onein which at least one atom is replaced by an atom having the same atomicnumber but an atomic mass different from the atomic mass usually foundin nature. Examples of isotopes that can be incorporated into compoundsof the invention include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorus, sulphur, fluorine and chlorine such as ²H, ³H, ¹³C, ¹⁴C,¹⁵N, ¹⁷O, ¹⁸O, ³¹P, ³²P, ³⁵S, ¹⁸F and ³⁶Cl, respectively. Certainisotopic variations of the invention, for example, those in which aradioactive isotope such as ³H or ¹⁴C is incorporated, are useful indrug and/or substrate tissue distribution studies. Tritiated, i.e. ³H,and carbon-14, i.e. ¹⁴C isotopes are particularly preferred for theirease of preparation and detectability. Further, substitution withisotopes such as deuterium, i.e. ²H, may afford certain therapeuticadvantages resulting from greater metabolic stability, for example,increased in vivo half-life or reduced dosage requirements and hence maybe preferred in some circumstances. Isotopic variations of the compoundsof the invention can generally be prepared by conventional proceduressuch as by the methods or preparations described in the Examples andPreparations hereafter using appropriate isotopic variations of suitablereagents.

[0095] Compounds of the invention may be prepared, in known manner in avariety of ways. In the following reaction schemes and hereafter, unlessotherwise stated, R¹ to R¹³, Z and Y are as defined in the first aspect.These processes form further aspects of the invention.

[0096] Throughout the specification, general formulae are designated byRoman numerals I, II, III, IV etc. Subsets of these general formulae aredefined as Ia, Ib, Ic etc, . . . IVa, IVb, IVc etc.

[0097] Compounds of general formula (I) may be prepared from compoundsof formula (II) by reaction with an amine of general formula HNR¹R², orwith a suitable salt form thereof, together with a hydride reducingagent in a suitable solvent (see Scheme 1). When either R¹ or R² ishydrogen, suitable solvents include protic solvents such as ethanol, andsodium borohydride is an appropriate reducing agent as exemplified byExample 36 herein. When neither R¹ or R² are hydrogen,tetrahydrofuran/dichloromethane is a suitable solvent system and sodiumtriacetoxyborohydride is a suitable reducing agent. In such reactionsthe use of a salt form of HNR¹R², such as the hydrochloride ispreferable, and an auxiliary base, to aid solubility of the HNR¹R² salt,such as triethylamine may optionally be added along with acetic acid, asexemplified by Example 25 herein.

[0098] Compounds of formula (II) may be prepared in turn from thecoupling of compounds of general formula (IV) with aldehyde compounds ofgeneral formula (III), wherein L is a suitable leaving group such ashalogen (F, Cl, Br or I) or a sulfonate ester such astrifluoromethanesulfonate or methanesulfonate, preferably L is F or Cl.Such coupling reaction may be accomplished by techniques known in theart, such as via reaction with potassium carbonate in a suitable solventsuch as dimethylformamide under appropriate reaction conditions such aselevated temperature and in an inert atmosphere.

[0099] Thus according to a further aspect, the invention provides aprocess for preparing compounds of general formula (I) from compounds ofthe general formula (II).

[0100] Alternatively, R⁴ and/or R⁵ may be introduced after ethercoupling (see Scheme 2). Compounds of general formula (I) may beprepared from compounds of general formula (Ia), i.e. compounds ofgeneral formula (I) where R⁴ and R⁵ are hydrogen. Compounds of generalformula (Ia) may be prepared from (IIa) in an analogous fashion to thepreparation of (I) from (II) (see Scheme 1), while compounds of generalformula (IIa) may be prepared from (IV) and (IIIa) in an analogousfashion to the preparation of (II) (see Scheme 1).

[0101] Thus according to a further aspect, the invention provides aprocess for preparing compounds of general formula (I) from compounds ofthe general formula (Ia).

[0102] Methodologies for introducing R⁴ and/or R⁵ into compounds offormula (Ia) include:

[0103] i) Where R⁴/R⁵ are halogen, by reaction of (Ia) with a suitablehalogenating agent in an inert solvent which does not adversely affectthe reaction. Suitable halogenating agents includetrifluoromethanesulfonic acid and N-iodosuccinimide and suitable inertsolvents include dichloromethane.

[0104] ii) Where R⁴/R⁵ are —NO₂, by reaction of (Ia) with a suitablenitrating agent, such as an alkali metal nitrate, in a solvent whichdoes not adversely affect the reaction at, or below, room temperature.Suitable nitrating agents include trifluoromethanesulfonicacid/potassium nitrate and suitable solvents include trifluoroaceticacid.

[0105] iii) Where R⁴/R⁵ is —SO₂NR⁶R⁷ by reaction of an intermediatesulfonyl chloride with the requisite amine of formula HNR⁶R⁷ in asuitable solvent. Suitable solvents include a mixture of water anddichloromethane and the reactions are generally performed at or belowroom temperature. The intermediate sulfonyl chlorides may be preparedfrom compounds of formula (Ia) by reaction with chlorosulfonic acidunder low temperature conditions in the presence of a solvent which doesnot adversely affect the reaction, either with or without subsequenttreatment with a chlorinating agent such as phosphorus oxychloride,phosphorus pentachloride, oxalyl chloride or thionyl chloride in asolvent which does not adversely affect the reaction. Suitable solventsfor the reaction with chlorosulfonic acid include trifluoroacetic acidand a typical reaction temperature is 0° C. Suitable solvents for thereaction with chlorinating agents include acetonitrile and suitableconditions include at reflux, as illustrated in Example 12 herein.

[0106] For example, compounds of formula (Iq), where R⁵ is —SO₂NR⁶R⁷,may be prepared via the intermediate sulfonyl chlorides (XVIII) fromcompounds of formula (Ia) by reaction of (Ia) with chlorosulfonic acid,either with or without subsequent treatment with a chlorinating agentsuch as phosphorus oxychloride, phosphorus pentachloride, oxalylchloride or thionyl chloride, followed by reaction with HNR⁶R⁷ (seescheme 2a). Reaction conditions typically comprise low temperature. Thereaction can take place either neat, i.e. in the absence of solvent, orin the presence of an inert solvent which does not adversely affect thereaction. The intermediate sulfonyl chloride (XVII) may be isolated,purified and then reacted with HNR⁶R⁷, alternatively it may be generatedin situ, without isolation, and then reacted with HNR⁶R⁷.

[0107] Thus according to a further aspect, the invention provides aprocess for preparing compounds of general formula (I) from compounds ofthe general formula (II). In a preferred embodiment, there is provided aprocess for preparing compounds of formula (Iq) by reacting compounds offormula (Ia) in a suitable solvent, with chlorosulfonic acid, eitherwith or without subsequent treatment with a chlorinating agent such asphosphorus oxychloride, phosphorus pentachloride, oxalyl chloride orthionyl chloride, to give compounds of formula (XVIII) followed byreaction with HNR⁶R⁷ to give compounds of formula (Iq). Preferablycompounds of formula (XVIII) are generated in situ and reacted withHNR⁶R⁷ without isolation.

[0108] Alternatively, compounds of general formula (I) having aparticular R⁴/R⁵ substituent may be converted into other compounds offormula (I) using known techniques. For example:

[0109] i) When R⁴/R⁵ is halogen such as chloro, bromo or iodo, it may beconverted to cyano via reaction with a cyanide salt in the presence of aPd(0) or (II)catalyst in a high boiling solvent at elevatedtemperatures. Suitable Pd catalysts include palladiumtetrakis(triphenylphosphine), suitable cyanide salts include Zn(CN)₂ andsuitable high boiling solvents which do not adversely affect thereaction include dimethylformamide as exemplified by Example 78 herein;

[0110] ii) When R⁴/R⁵ is halogen such as chloro, bromo or iodo, it maybe converted to the corresponding ester —CO₂R by treatment with carbonmonoxide at high pressure with a Pd(0) or (II) catalyst, in an alcoholsolvent (ROH wherein R is C₁-C₄ alkyl), in the presence of a base atelevated temperatures. For example the reaction may be carried out atpressures in the region of about 100 p.s.i, whilst suitable Pd catalystsinclude dichlorobis(triphenylphosphine) palladium (II), suitable basesinclude triethylamine and suitable alcohol solvents include methanol asexemplified by Preparation 50 herein;

[0111] iii) When R⁴/R⁵ is nitro, it may be reduced to the corresponding—NH₂ group via treatment with a reducing agent in a protic solvent at,or above, room temperature. Suitable reducing agents include ironpowder/calcium chloride, suitable protic solvents include aqueousethanol and a typical reaction temperature is from about 70° C. to about100° C., preferably about 90° C., as exemplified by Example 103 herein;

[0112] iv) When R⁴/R⁵ is —NH₂, it may be converted to the corresponding—NHSO₂R⁹ group by reaction with a sulfonylating agent in the presence ofa base in an inert solvent which does not adversely affect the reactionat, or below, room temperature. Suitable sulfonylating agents includemethanesulfonyl chloride, suitable bases include triethylamine andsuitable inert solvents include dichloromethane as exemplified byExample 128 herein;

[0113] v) When R^(4/)R⁵ is a —NHSO₂R⁹ group, it may be converted to thecorresponding —NR⁸SO₂R⁹ group via treatment with an alkylating agent anda base in a suitable inert solvent. Examples of suitable alkylatingagents include methyl iodide, suitable bases include potassium carbonateand suitable inert solvents include acetonitrile, as exemplified byPreparation 88 herein;

[0114] vi) When R⁴/R⁵ is a nitrile —CN, it may be converted to thecorresponding —C(O)NH₂ group by hydrolysis under basic, oxidative oracid conditions. Basic hydrolysis is preferably conducted with ahydroxide salt such as potassium hydroxide in a protic solvent such ast-butanol at elevated temperatures, as exemplified in Example 79 herein.

[0115] vii) When R⁴/R⁵ is an ester —CO₂R, it may be reduced to thecorresponding alcohol group —CH₂OH via treatment with a hydride reducingagent, such as lithium aluminium hydride, as exemplified by Preparation69 herein;

[0116] viii) When R⁴/R⁵ is an ester —CO₂R, it may be converted to thecorresponding acid —CO₂H by treatment with a suitable hydroxide salt inthe presence of water and a suitable co-solvent. Suitable hydroxidesalts include lithium hydroxide and suitable co-solvents includetetrahydrofuran, as exemplified by Preparation 55 herein;

[0117] ix) When R⁴/R⁵ is an acid —CO₂H, it may be converted to thecorresponding amide —CONR⁶R⁷ by treatment with a coupling agent, a baseand an amine HNR⁶R⁷ in a suitable inert solvent which does not adverselyaffect the reaction. Suitable coupling agents include1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in thepresence of 1-hydroxybenzotriazole, suitable bases include triethylamineand suitable solvents include dichloromethane, as exemplified byPreparation 59 herein;

[0118] x) When R⁴/R⁵ is halogen such as chloro, bromo or iodo, it may beconverted to an α,β-unsaturated amide, by treatment with acrylamide, aPd(0) or (II) catalyst and a suitable base, in an inert solvent whichdoes not adversely affect the reaction, at elevated temperatures.Suitable Pd catalysts include palladium (II) acetate in the presence oftri(o-tolyl)phosphine, suitable bases include triethylamine and suitableinert solvents include acetonitrile as exemplified by Example 50 herein;

[0119] xi) When R⁴/R⁵ is an α,β-unsaturated amide, it may be convertedto —CH₂CH₂CO₂NH₂, by treatment with a suitable reducing agent at anappropriate temperature, in a suitable solvent which does not adverselyaffect the reaction. Suitable reducing agents include samarium diiodideat room temperature and suitable solvents include tetrahydrofurancontaining a small amount of water, as exemplified by Example 51 herein;

[0120] xii) When R⁴/R⁵ is —CH₂OH, it may be converted to —CH₂NR⁸SO₂R⁹ bymeans of a Mitsunobu reaction at an appropriate temperature, in asuitable solvent which does not adversely affect the reaction. Suitablereagents include diethyl azodicarboxylate, triphenylphosphine andtert-butyl methylsulfonylcarbamate, 0° C. is a suitable reactiontemperature and tetrahydrofuran is a suitable solvent as exemplified byPreparation 72 herein;

[0121] Alternatively, compounds of general formula (I) having aparticular NR¹R² group may be converted into other compounds of generalformula (I) having a different NR¹R² group. For example:

[0122] i) Compounds of formula (Ib) wherein either R¹ or R² is hydrogen,can be converted into a compound of formula (Ic) wherein neither R¹ norR² are hydrogen, by reaction of the compound of formula (Ib) with analdehyde and a hydride reducing agent. Suitable aldehydes includeformaldehyde, suitable reducing agents include sodiumtri(acetoxy)borohydride and the reaction is preferably conducted in asolvent which does not interfere with the reaction, such asdichloromethane at or below room temperature, as exemplified by Example12 herein.

[0123] ii) Compounds of formula (Ib) wherein R¹ or R² is hydrogen, canbe converted into a compound of formula (Ic) wherein R¹ or R² is methyl,by reaction of the compound of formula (Ib) with a formylating agent ina suitable solvent, followed by subsequent reduction of the intermediateN-formyl compound with a hydride reducing agent in an inert solvent,preferably at elevated temperature. Suitable formylating agents includepentafluorophenyl formate (formed from formic acid, pentafluorophenoland dicyclohexylcarbodiimide) and suitable solvents for the formylationinclude dichloromethane. Suitable reducing agents includeborane-tetrahydrofuran complex and suitable inert solvents for thereduction include tetrahydrofuran as exemplified by Example 110 herein.

[0124] Alternatively, compounds of general formula (I) may be preparedfrom compounds of formula V (see Scheme 3) wherein L is as defined forScheme 1 and T is a group which can be converted into CH₂NR¹R². Examplesof suitable T substitutents include: —CO₂R¹⁰, —CN and —C(O)NR¹R².

[0125] Methodologies for converting compounds of formula (V) to (I),include:

[0126] i) Where T is —CO₂R¹⁰ and R¹⁰=methyl or ethyl, by reaction withan amine of general formula NHR¹R² to form an amide, followed byreduction to provide an amine.

[0127] ii) Where T═—CN, by reduction to its corresponding amine offormula —CH₂NH₂.

[0128] iii) Where T═—C(O)NR¹R², by reduction to provide an amine.

[0129] Compounds of general formula (V) may be prepared in turn by thecoupling of compounds of general formula (VI) and compounds of thegeneral formula (IV). Reagents and conditions for such couplingreactions are as previously defined for the coupling of compounds ofgeneral formulae (IV) and (III) in Scheme 1.

[0130] Compounds of general formula (VI) may be prepared in turn fromcompounds of general formula (VII) (see Scheme 4).

[0131] Compounds of formula (VI) may be prepared by aromaticelectrophilic substitution of compounds of formula (VII) to givecompounds of formula (VI) directly. Alternatively compounds of formula(VI) may be prepared in two or more steps; aromatic electrophilicsubstitution of compounds of formula (VII) to give intermediatecompounds which then undergo further reaction to give compounds offormula (VI). The intermediate compounds may be isolated or generated insitu without isolation. A preferred route is shown in Scheme 5.

[0132] Compounds of formula (VII) are reacted with sulfonyl chloride togive compounds of formula (VII) followed by reaction with NHR⁶R⁷ to givecompounds of formula (VIa).

[0133] According to further aspects, the invention provides compounds offormulae (II), (IIa) and (V) as defined above.

[0134] Compounds of formulae (III), (IIIa), (IV), (VI) or (VII) areeither known and available from commercial sources or are available fromcommercially available materials using known techniques (see Exampleshereinafter).

[0135] It will be apparent to those skilled in the art that sensitivefunctional groups may need to be protected and deprotected duringsynthesis of a compound of formula I. This may be achieved byconventional techniques, for example as described in ‘Protective Groupsin Organic Synthesis’, 3rd edition, by T W Greene and P G M Wuts, JohnWiley and Sons Inc, 1999. Example 35 provides one example of aprotecting group strategy employed in the synthesis of a compound of thepresent invention.

[0136] The skilled chemist will appreciate that diaryl ethers may beprepared using a number of synthetic methodologies. For a review ofmethodologies see J S Sawyer, Tetrahedron, 56 (2000) 5045-5065,incorporated herein by reference.

[0137] The compounds of the invention are useful because they havepharmacological activity in mammals, including humans. Moreparticularly, they are useful in the treatment or prevention of adisorder in which the regulation of monoamine transporter function isimplicated. Disease states that may be mentioned include hypertension,depression (e.g. depression in cancer patients, depression inParkinson's patients, postmyocardial infarction depression, subsyndromalsymptomatic depression, depression in infertile women, paediatricdepression, major depression, single episode depression, recurrentdepression, child abuse induced depression, post partum depression andgrumpy old man syndrome), generalized anxiety disorder, phobias (e.g.agoraphobia, social phobia and simple phobias), posttraumatic stresssyndrome, avoidant personality disorder, premature ejaculation, eatingdisorders (e.g. anorexia nervosa and bulimia nervosa), obesity, chemicaldependencies (e.g. addictions to alcohol, cocaine, heroin,phenobarbital, nicotine and benzodiazepines), cluster headache,migraine, pain, Alzheimer's disease, obsessive-compulsive disorder,panic disorder, memory disorders (e.g. dementia, amnestic disorders, andage-related cognitive decline (ARCD)), Parkinson's diseases (e.g.dementia in Parkinson's disease, neuroleptic-induced parkinsonism andtardive dyskinesias), endocrine disorders (e.g. hyperprolactinaemia),vasospasm (particularly in the cerebral vasculature), cerebellar ataxia,gastrointestinal tract disorders (involving changes in motility andsecretion), negative symptoms of schizophrenia, premenstrual syndrome,fibromyalgia syndrome, stress incontinence, Tourette's syndrome,trichotillomania, kleptomania, male impotence, attention deficithyperactivity disorder (ADHD), chronic paroxysmal hemicrania, headache(associated with vascular disorders), emotional lability, pathologicalcrying, sleeping disorder (cataplexy) and shock.

[0138] Disorders of particular interest include depression, attentiondeficit hyperactivity disorder, obsessive-compulsive disorder,post-traumatic stress disorder, substance abuse disorders and sexualdysfunction including (in particular) premature ejaculation. Prematureejaculation may be defined as persistent or recurrent ejaculationbefore, upon or shortly after penile penetration of a sexual partner. Itmay also be defined as ejaculation occurring before the individualwishes [see ‘The Merck Manual’, 16^(th) edition, p 1576, published byMerck Research Laboratories, 1992].

[0139] Thus, according to further aspects, the invention provides:

[0140] i) a compound of the invention for use as a pharmaceutical;

[0141] ii) the use of a compound of the invention in the manufacture ofa medicament for the treatment or prevention of a disorder in which theregulation of monoamine transporter function is implicated, for exampledepression, attention deficit hyperactivity disorder,obsessive-compulsive disorder, post-traumatic stress disorder, substanceabuse disorders or sexual dysfunction including premature ejaculation;

[0142] iii) the use of a compound of the invention in the manufacture ofa medicament for the treatment or prevention of premature ejaculation;

[0143] iv) a method of treatment or prevention of depression, attentiondeficit hyperactivity disorder, obsessive-compulsive disorder,post-traumatic stress disorder, substance abuse disorders or sexualdysfunction including premature ejaculation, which comprisesadministering a therapeutically effective amount of a compound of theinvention to a patient in need of such treatment or prevention;

[0144] v) a method of increasing ejaculatory latency which comprises theadministration of an effective amount of a compound of the invention toa male desiring increased ejaculatory latency; and

[0145] vi) a compound of the invention for the treatment or preventionof a disorder in which the regulation of monoamine transporter functionis implicated, for example depression, attention deficit hyperactivitydisorder, obsessive-compulsive disorder, post-traumatic stress disorder,substance abuse disorders or sexual dysfunction including prematureejaculation.

[0146] vii) a compound of the invention for treating prematureejaculation.

[0147] It is to be appreciated that all references herein to treatmentinclude curative, palliative and prophylactic treatment.

[0148] The compounds of the invention may be administered alone or aspart of a combination therapy. If a combination of active agents areadministered, then they may be administered simultaneously, separatelyor sequentially. In particular, the compounds of the invention may becombined with the following preferably for the treatment of PE:

[0149] i) Alpha-blockers (e.g. phentolamine, doxazasim, tamsulosin,terazasin, prazasin and Example 19 of WO9830560. A possible rationalefor alpha-blockers treating premature ejaculation is as follows.Muscular activity of the ejaculatory smooth muscles (vas deferens,seminal vesicles and urethra) are controlled by the sympathetic nervoussystem through the release of noradrenalin. Noradrenalin acts on thealpha 1 adrenoreceptors, stimulating muscle contractions, leading toseminal emission and subsequently ejaculation. Blocking these receptorswill therefore inhibit ejaculation.

[0150] ii) Apomorphine—teachings on the use of apomorphine as apharmaceutical may be found in U.S. Pat. No. 5,945,117.

[0151] iii) Dopamine D2 agonists (e.g. Premiprixal, Pharmacia Upjohncompound number PNU95666).

[0152] iv) Melanocortin receptor agonists (e.g. Melanotan II).

[0153] v) PGE1 receptor agonists (e.g. alprostadil).

[0154] vi) Mono amine transport inhibitors, particularly NoradrenalineRe-uptake Inhibitors (NRIs) (e.g. Reboxetine), other Serotonin Re-uptakeInhibitors (SRIs) (e.g. paroxetine) or Dopamine Re-uptake Inhibitors(DRIs).

[0155] vii) 5-HT3 antagonists (e.g. ondansetron and granisetron). Apossible rationale for 5-HT3 antagonists treating premature ejaculationis as follows. 5-HT3 receptors, present in the lumen of the posteriorportion of the urethra, are stimulated by 5-HT in the semen duringseminal emission, leading to a sensitisation of the spinal relex pathwaywhich leads to ejaculation. Therefore, an antagonist would prevent thissensitisation and thus delay ejaculation.

[0156] viii) PDE inhibitors such as PDE2 (e.g.erythro-9-(2-hydroxyl-3-nonyl)-adenine) and Example 100 of EP0771799-incorporated herein by reference) and in particular a PDE5inhibitor (e.g. sildenafil,1-{[3-(3,4-dihydro-5-methyl-4-oxo-7-propylimidazo[5,1-f]-as-trazin-2-yl)-4-ethoxyphenyl]sulfonyl}-4-ethylpiperazinei.e. vardenafil/Bayer BA 38-9456 or IC351 (see structure below, lcosLilly)). A possible rationale for PDE inhibitors treating prematureejaculation is as follows. c AMP and CGMP levels in the ejaculatorysmooth muscles regulate muscle tone of these ejaculatory muscles and sodelay ejaculation.

[0157] ix)Potassium channel openers.

[0158] x) P2X purinergic receptor antagonists.

[0159] xi) Endothelin receptor antagonists

[0160] For human use the compounds of the invention can be administeredalone but in human therapy will generally be administered in admixturewith a suitable pharmaceutical excipient, diluent or carrier selectedwith regard to the intended route of administration and standardpharmaceutical practice.

[0161] For example, the compounds of the invention, can be administeredorally, buccally or sublingually in the form of tablets, capsules(including soft gel capsules), ovules, elixirs, solutions orsuspensions, which may contain flavouring or colouring agents, forimmediate-, delayed-, modified-, sustained-, dual-, controlled-releaseor pulsatile delivery applications. The compounds of the invention mayalso be administered via intracavernosal injection. The compounds of theinvention may also be administered via fast dispersing or fastdissolving dosage forms.

[0162] Such tablets may contain excipients such as microcrystallinecellulose, lactose, sodium citrate, calcium carbonate, dibasic calciumphosphate, glycine, and starch (preferably corn, potato or tapiocastarch), disintegrants such as sodium starch glycollate, croscarmellosesodium and certain complex silicates, and granulation binders such aspolyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC),hydroxypropylcellulose (HPC), sucrose, gelatin and acacia. Additionally,lubricating agents such as magnesium stearate, stearic acid, glycerylbehenate and talc may be included.

[0163] Solid compositions of a similar type may also be employed asfillers in gelatin capsules. Preferred excipients in this regard includelactose, starch, a cellulose, milk sugar or high molecular weightpolyethylene glycols. For aqueous suspensions and/or elixirs, thecompounds of the invention, and their pharmaceutically acceptable salts,may be combined with various sweetening or flavouring agents, colouringmatter or dyes, with emulsifying and/or suspending agents and withdiluents such as water, ethanol, propylene glycol and glycerin, andcombinations thereof.

[0164] Modified release and pulsatile release dosage forms may containexcipients such as those detailed for immediate release dosage formstogether with additional excipients that act as release rate modifiers,these being coated on and/or included in the body of the device. Releaserate modifiers include, but are not exclusively limited to,hydroxypropylmethyl cellulose, methyl cellulose, sodiumcarboxymethylcellulose, ethyl cellulose, cellulose acetate, polyethyleneoxide, Xanthan gum, Carbomer, ammonio methacrylate copolymer,hydrogenated castor oil, carnauba wax, paraffin wax, cellulose acetatephthalate, hydroxypropylmethyl cellulose phthalate, methacrylic acidcopolymer and mixtures thereof. Modified release and pulsatile releasedosage forms may contain one or a combination of release rate modifyingexcipients. Release rate modifying excipients may be present both withinthe dosage form i.e. within the matrix, and/or on the dosage form, i.e.upon the surface or coating.

[0165] Fast dispersing or dissolving dosage formulations (FDDFs) maycontain the following ingredients: aspartame, acesulfame potassium,citric acid, croscarmellose sodium, crospovidone, diascorbic acid, ethylacrylate, ethyl cellulose, gelatin, hydroxypropylmethyl cellulose,magnesium stearate, mannitol, methyl methacrylate, mint flavouring,polyethylene glycol, fumed silica, silicon dioxide, sodium starchglycolate, sodium stearyl fumarate, sorbitol, xylitol. The termsdispersing or dissolving as used herein to describe FDDFs are dependentupon the solubility of the drug substance used i.e. where the drugsubstance is insoluble a fast dispersing dosage form can be prepared andwhere the drug substance is soluble a fast dissolving dosage form can beprepared.

[0166] The compounds of the invention can also be administeredparenterally, for example, intravenously, intra-arterially,intraperitoneally, intrathecally, intraventricularly, intraurethrally,intrasternally, intracranially, intramuscularly or subcutaneously, orthey may be administered by infusion techniques. For such parenteraladministration they are best used in the form of a sterile aqueoussolution which may contain other substances, for example, enough saltsor glucose to make the solution isotonic with blood. The aqueoussolutions should be suitably buffered (preferably to a pH of from 3 to9), if necessary. The preparation of suitable parenteral formulationsunder sterile conditions is readily accomplished by standardpharmaceutical techniques well known to those skilled in the art.

[0167] The following dosage levels and other dosage levels herein arefor the average human subject having a weight range of about 65 to 70kg. The skilled person will readily be able to determine the dosagelevels required for a subject whose weight falls outside this range,such as children and the elderly.

[0168] For oral and parenteral administration to human patients, thedaily dosage level of the compounds of the invention or salts orsolvates thereof will usually be from 10 to 500 mg (in single or divideddoses).

[0169] Thus, for example, tablets or capsules of the compounds of theinvention may contain from 5 mg to 250 mg of active compound foradministration singly or two or more at a time, as appropriate. Thephysician in any event will determine the actual dosage which will bemost suitable for any individual patient and it will vary with the age,weight and response of the particular patient. The above dosages areexemplary of the average case. There can, of course, be individualinstances where higher or lower dosage ranges are merited and such arewithin the scope of this invention. The skilled person will alsoappreciate that, in the treatment of certain conditions (including PE),compounds of the invention may be taken as a single dose on an “asrequired” basis (i.e. as needed or desired).

[0170] Example Tablet Formulation

[0171] In general a tablet formulation could typically contain betweenabout 0.01 mg and 500 mg of a compound of the invention whilst tabletfill weights may range from 50 mg to 1000 mg. An example formulation fora 10 mg tablet is illustrated: Ingredient % w/w Compound of theinvention 10.000* Lactose 64.125 Starch 21.375 Croscarmellose Sodium3.000 Magnesium Stearate 1.500

[0172] The compounds of the invention can also be administeredintranasally or by inhalation and are conveniently delivered in the formof a dry powder inhaler or an aerosol spray presentation from apressurised container, pump, spray or nebulizer with the use of asuitable propellant, e.g. dichlorodifluoromethane,trichlorofluoromethane, dichlorotetra-fluoro-ethane, a hydrofluoroalkanesuch as 1,1,1,2-tetrafluoroethane (HFA 134A [trade mark]) or1,1,1,2,3,3,3-heptafluoropropane (HFA 227EA [trade mark]), carbondioxide or other suitable gas. In the case of a pressurised aerosol, thedosage unit may be determined by providing a valve to deliver a meteredamount. The pressurised container, pump, spray or nebulizer may containa solution or suspension of the active compound, e.g. using a mixture ofethanol and the propellant as the solvent, which may additionallycontain a lubricant, e.g. sorbitan trioleate. Capsules and cartridges(made, for example, from gelatin) for use in an inhaler or insufflatormay be formulated to contain a powder mix of a compound of the inventionand a suitable powder base such as lactose or starch.

[0173] Aerosol or dry powder formulations are preferably arranged sothat each metered dose or “puff” contains from 1 to 50 mg of a compoundof the invention for delivery to the patient. The overall daily dosewith an aerosol will be in the range of from 1 to 50 mg which may beadministered in a single dose or, more usually, in divided dosesthroughout the day.

[0174] The compounds of the invention may also be formulated fordelivery via an atomiser. Formulations for atomiser devices may containthe following ingredients as solubilisers, emulsifiers or suspendingagents: water, ethanol, glycerol, propylene glycol, low molecular weightpolyethylene glycols, sodium chloride, fluorocarbons, polyethyleneglycol ethers, sorbitan trioleate, oleic acid.

[0175] Alternatively, the compounds of the invention can be administeredin the form of a suppository or pessary, or they may be appliedtopically in the form of a gel, hydrogel, lotion, solution, cream,ointment or dusting powder. The compounds of the invention may also bedermally or transdermally administered, for example, by the use of askin patch. They may also be administered by the ocular, pulmonary orrectal routes.

[0176] For ophthalmic use, the compounds can be formulated as micronizedsuspensions in isotonic, pH adjusted, sterile saline, or, preferably, assolutions in isotonic, pH adjusted, sterile saline, optionally incombination with a preservative such as a benzylalkonium chloride.Alternatively, they may be formulated in an ointment such as petrolatum.

[0177] For application topically to the skin, the compounds of theinvention can be formulated as a suitable ointment containing the activecompound suspended or dissolved in, for example, a mixture with one ormore of the following: mineral oil, liquid petrolatum, white petrolatum,propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifyingwax and water. Alternatively, they can be formulated as a suitablelotion or cream, suspended or dissolved in, for example, a mixture ofone or more of the following: mineral oil, sorbitan monostearate, apolyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters, wax,cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[0178] The compounds of the invention may also be used in combinationwith a cyclodextrin. Cyclodextrins are known to form inclusion andnon-inclusion complexes with drug molecules. Formation of adrug-cyclodextrin complex may modify the solubility, dissolution rate,bioavailability and/or stability property of a drug molecule.Drug-cyclodextrin complexes are generally useful for most dosage formsand administration routes. As an alternative to direct complexation withthe drug the cyclodextrin may be used as an auxiliary additive, e.g. asa carrier, diluent or solubiliser. Alpha-, beta- and gamma-cyclodextrinsare most commonly used and suitable examples are described inWO-A-91/11172, WO-A-94/02518 and WO-A-98/55148.

[0179] For oral or parenteral administration to human patients the dailydosage levels of compounds of the invention will be from 0.01 to 30mg/kg (in single or divided doses) and preferably will be in the range0.01 to 5 mg/kg. Thus tablets will contain 1 mg to 0.4 g of compound foradministration singly or two or more at a time, as appropriate. Thephysician will in any event determine the actual dosage which will bemost suitable for any particular patient and it will vary with the age,weight and response of the particular patient. The above dosages are, ofcourse only exemplary of the average case and there may be instanceswhere higher or lower doses are merited, and such are within the scopeof the invention.

[0180] Oral administration is preferred. Preferably, administrationtakes place shortly before an effect is required.

[0181] For veterinary use, a compound of the invention is administeredas a suitably acceptable formulation in accordance with normalveterinary practice and the veterinary surgeon will determine the dosingregimen and route of administration which will be most appropriate for aparticular animal.

[0182] Thus according to a further aspect, the invention provides apharmaceutical formulation containing a compound of the invention and apharmaceutically acceptable adjuvant, diluent or carrier.

[0183] The invention is illustrated by the following non-limitingexamples in which the following abbreviations and definitions are used:Arbocel ® filter agent br broad Boc tert-butoxycarbonyl CDIcarbonyldiimidazole δ chemical shift d doublet Δ heat DCCIdicyclohexylcarbodiimide DCM dichloromethane DMF N,N-dimethylformamideDMSO dimethylsulfoxide ES⁺ electrospray ionisation positive scan ES⁻electrospray ionisation negative scan Ex Example h hours HOBt1-hydroxybenzotriazole HPLC high pressure liquid chromatography m/z massspectrum peak min minutes MS mass spectrum NMR nuclear magneticresonance Prec precursor Prep preparation q quartet s singlet t tripletTf trifluoromethanesulfonyl TFA trifluoroacetic acid THF tetrahydrofuranTLC thin layer chromatography TS⁺ thermospray ionisation positive scanWSCDI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

[0184]¹H Nuclear magnetic resonance (NMR) spectra were in all casesconsistent with the proposed structures. Characteristic chemical shifts(δ) are given in parts-per-million downfield from tetramethylsilaneusing conventional abbreviations for designation of major peaks: e.g. s,singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad.The following abbreviations have been used for common solvents: CDCl₃,deuterochloroform; DMSO, dimethylsulfoxide. The abbreviation psi meanspounds per square inch and LRMS means low resolution mass spectrometry.Where thin layer chromatography (TLC) has been used it refers to silicagel TLC using silica gel 60 F₂₅₄ plates, R_(f) is the distance travelledby a compound divided by the distance travelled by the solvent front ona TLC plate. Melting points were determined using a Perkin Elmer DSC7 ata heating rate of 20° C./minute).

[0185] Where indicated, compounds were characterised as theirhydrochloride salts. A typical procedure for formation of hydrochloridesalts is given in Example 12. The procedure can be carried out withother solvents e.g. diethyl ether or DCM.

[0186] Commercial starting materials were obtained from Aldrich ChemicalCo, Lancaster Synthesis Ltd or Acros Organics.

[0187] The amide of Preparation 8 (760 mg, 2.07 mmol) was slurried inTHF (10 mL) and the resulting suspension was treated withborane.tetrahydrofuran complex (1M solution in THF, 6.22 mL, 6.22 mmol)at room temperature. The resulting solution was heated at reflux for 5hours under an atmosphere of dry nitrogen. The reaction was cooled toroom temperature and treated cautiously with 6M HCl solution (6 mL). Theresulting mixture was heated at reflux for 30 min. After cooling to roomtemperature the mixture was diluted with water (10 mL) and basified bycautious addition of potassium carbonate solid. The aqueous layer wasextracted with EtOAc (20 mL) which gave a precipitate in the organiclayer, and the aqueous layer was further extracted with DCM (2×20 mL).The EtOAc fraction was washed with 2M NaOH (20 mL) giving a cleartwo-phase separation and the basic layer was extracted with DCM (4×25mL). All the organic fractions were combined and washed with brine (20mL), dried (MgSO₄) and evaporated to a colourless oil. Purification byflash chromatography [SiO₂; 95:5:0.5 to 90:10:1 (EtOAc/MeOH/880 NH₃)]afforded a white powder of the desired amine (646 mg, 89%). δ_(H) (300MHz, d₆-DMSO) 2.26 (3H, d), 2.32 (3H, d), 2.45 (3H, d), 3.75 (2H, d),6.90 (3H, m), 7.25 (3H, br), 7.67 (1H, t) 7.98 (1H, d); MS m/z (TS⁺) 353(MH⁺).

[0188] Compounds of formula Id, i.e. compounds of general formula Iwhere R¹ is methyl, R² is hydrogen and R⁵ is —SO₂NH₂, shown in Table 1were prepared in an analogous fashion to Example 1 from the precursorsindicated. TABLE 1

Example Precursor

data 2 Prep 9

HCl salt: δ_(H) (CD₃OD, 400 MHz) 2.80 (3H, s), 3.42 (2H, m), 4.41 (2H,s), 6.86-7.00 (2H, m), 7.09 (1H, s), 7.23 (1H, d), 7.90 (1H, d), 8.05(1H, s); MS m/z (TS⁺) 351 (MH⁺) 3 Prep 12

HCl salt: δ_(H) (CD₃OD, 300 MHz) 2.54 (3H, s), 2.82 (3H, s), 4.43 (2H,s), 7.00 (1H, d), 7.20 (1H, d), 7.34 (1H, s), 7.42 (1H, d), 7.95 (1H,d), 8.11 (1H, s); MS m/z (TS⁺) 373 (MH⁺) 4 Prep 11

HCl salt: δ_(H) (CD₃OD, 400 MHz) 2.45 (3H, s), 2.73 (3H, s), 5.44 (2H,s), 6.97 (3H, m), 7.42 (1H, m), 7.89 (1H, m), 8.03 (1H, s); MS m/z (ES⁺)357 (MH⁺) 5 Prep 10

HCl salt: δ_(H) (CD₃OD, 400 MHz) 2.79 (3H, s), 3.18 (2H, m), 4.38 (2H,s), 4.41 (2H, m), 6.68 (2H, m), 6.97 (1H, d), 7.13 (1H, d), 7.91 (1H,d), 8.03 (1 H, s); MS m/z (TS⁺) 367 (MH⁺) 6 Prep 13

HCl salt: δ_(H) (CD₃OD, 400 MHz) 2.78 (3H, s), 3.15 (2H, m), 4.38 (4H,m), 6.79 (1H, d), 6.85 (3H, m), 7.84 (1H, d), 8.00 (1H, s); MS m/z (ES⁺)367 (MH⁺) 7 Prep 14

HCl salt: δ_(H) (CD₃OD, 400 MHz) 2.81 (3H, s), 4.43 (2H, s), 5.09 (4K,s), 6.93 (1H, d), 7.12 (2H, s + d), 7.40 (1H, d), 7.90 (1H, d), 8.08(1H, s); MS m/z (TS⁺) 335 (MH⁺) 8 Prep 15

HCl salt: δ_(H) (CD₃OD, 400 MHz) 2.16 (2H, m), 2.80 (3H, s), 2.92 (4H,t), 4.40 (2H, s), 6.86 (1H, d), 6.94 (1H, d), 7.03 (1H, s), 7.30 (1H,d), 7.88 (1H, d), 8.03 (1H, s); MS m/z (TS⁺) 333 (MH⁺) 9 Prep 16

HCl salt: δ_(H) (CD₃OD, 400 MHz) 2.32 (3H, s), 2.43 (3H, s), 2.81 (3H,s), 4.41 (2H, s), 6.84 (1H, d), 6.91 (1H, d), 7.06 (1H, s), 7.24 (1H,d), 7.89 (1H, d), 8.05 (1H, s); MS m/z (ES⁺) 352 (MH⁺) 10 Prep 17

HCl salt: δ_(H) (CD₃OD, 400 MHz) 2.78 (3H, s), 4.21 (4H, s), 4.39 (2H,s), 6.89 (1H, d), 7.01 (1H, d), 7.08 (1H, s), 7.38 (1H, d), 7.85 (1H,d), 8.02 (1H, s); MS m/z (TS⁺) 351 (MH⁺) 11 Prep 18

δ_(H) (CD₃OD, 400 MHz) 2.76 (3H, s), 3.30 (2H, m), 3.42 (2H, m), 4.33(2H, s), 6.90 (1H, d), 6.94 (1H, d), 7.00 (1H, s), 7.29 (2H, d), 7.89(1H, d), 8.04 (1H, s); MS m/z (ES⁺) 351 (MH⁺), (ES⁻) 349 (M − H⁺)

EXAMPLES 12 and 133-[(Dimethylamino)methyl]-4-[3-methyl-4-(methylsulfanyl)phenoxy]-benzenesulfonamide(Example 12) and3-[(dimethylamino)methyl]-N-methyl-4-[3-methyl-4-(methylsulfanyl)phenoxy]benzenesulfonamide(Example 13)

[0189]

[0190] Formaldehyde (37% aq. solution, 282 μL, 3.76 mmol) was added to asuspension of the secondary amine from Example 1 (409 mg, 1.16 mmol) inDCM (20 mL) at room temperature under nitrogen. The resulting mixturewas stirred for 15 minutes before the addition of sodiumtriacetoxyborohydride (984 mg, 4.64 mmol). The resulting reactionmixture was stirred for 5 hours before being basified with saturatedNaHCO₃ solution (10 mL) and extracted with DCM (3×20 mL). The organiclayers were washed with brine (10 mL), dried (MgSO₄) and evaporated to ayellow oil. This was purified by HPLC (Phenomonex Luna C₁₈ 75×4.6 mmcolumn, CH₃CN, H₂O, TFA). Fractions containing the major product wereevaporated and the residue was treated with sat. NaHCO₃ solution (5 mL),and extracted with DCM (3×30 mL). The combined organic fractions werewashed with brine (30 mL), dried (MgSO₄) and evaporated to give a whitefoam (155 mg, 36%) of Example 12; δ_(H) (300 MHz, CDCl₃) 2.30 (6H, s),2.35 (3H, s), 2.48 (3H, s), 3.60 (2H, s), 6.83 (3H, m), 7.20 (1H, m),7.28 (2H, s), 7.74 (1H, d), 8.08 (1H, s); MS m/z (TS+) 367 (MH⁺).

[0191] A minor product was also obtained after HPLC purification. Therelevant fractions were evaporated and the residue was treated with sat.NaHCO₃ solution (5 mL), and extracted with DCM (2×30 mL). The combinedorganic fractions were washed with brine (30 mL), dried (MgSO₄) andevaporated to a gum. This was taken up in DCM (5 mL), treated with 1Methereal HCl (2 mL) and evaporated to give a white powder (39 mg, 9%) ofExample 13; HCl salt: δ_(H) (CDCl₃, 300 MHz) 2.30 (6H, s), 2.35 (3H, s),2.48 (3H, s), 3.60 (2H, s), 6.83 (3H, m), 7.20 (1H, m), 7.28 (2H, s),7.74 (1H, d), 8.08 (1H, s); MS m/z (TS⁺) 381 (MH⁺).

[0192] In a repeat reaction, using 1 equivalent of formaldehyde to theamine of Example 1, Example 12 was obtained in 78% yield after columnchromatography [SiO₂; 95:5:0.5 to 90:10:1 (EtOAc/MeOH/880 NH₃)]. Thiswas taken up in EtOAc and converted to the HCl salt by the addition of1M ethereal HCl. The resulting precipitate was filtered and dried invacuo to give Example 12 HCl salt; m.p. 188° C.

[0193] Alternatively, Example 12 can also be formed from the amine ofExample 1 by the method of Example 110.

[0194] Example 12 was also prepared as follows.

[0195] A solution of the hydrochloride salt from Example 94 (20 g) intrifluoroacetic acid (100 mL) was slowly added to a solution ofchlorosulfonic acid (72 g) keeping the temperature between 0 and 5° C.After 1 h the reaction mixture was quenched slowly into water (200 mL),at 0-20° C. The mixture was then extracted with dichloromethane (200 mL)and separated. The aqueous layer was then extracted with dichloromethane(60 mL) and separated. The combined organic layers were washed withwater (200 mL). The layers were separated and the dichloromethaneremoved in vacuo to give a solid. Acetonitrile (240 mL) was added and tothis slurry was added phosphorus oxychloride (28.8 mL). The solution wasthen heated at reflux overnight. The reaction mixture was cooled to roomtemperature and quenched into a stirred mixture of ammonia (90 mL),dichloromethane (240 mL) and water (100 mL), keeping the temperaturebetween 0° C. and 10° C. The mixture was adjusted with ammonia (ifnecessary) to greater than pH8. After 15 mins the reaction mixture wasallowed to warm to room temperature and the layers separated. Theorganic layer was concentrated in vacuo to give a thick brown oil. Thiswas dissolved in acetone (100 mL) and slurried with carbon (Norit SXplus, 50% w/w) filtered and treated with another charge of carbon (NoritSX plus, 50% w/w). This mixture was again filtered and the solutionconcentrated, replacing with water (200 mL). The slurry was granulated,filtered and vacuum dried overnight to give the title product as acreamy white solid (yield 40%).

EXAMPLES 14 and 154-(2,3-Dihydro-1,4-benzoxathiin-7-yloxy)-3-[(dimethylamino)methyl]-benzenesulfonamideand4-(2,3-dihydro-1,4-benzoxathiin-7-yloxy)-3-[(dimethylamino)methyl]-N-methylbenzenesulfonamide

[0196]

[0197] These compounds were formed in an analogous fashion to Examples12 and 13 starting from the secondary amine of Example 5.

EXAMPLE 14

[0198] HCl salt: δ_(H) (CD₃OD, 400 MHz) 2.97 (6H, s), 3.18 (2H, m), 4.42(2H, m), 4.52 (2H, s), 6.68 (2H, d), 6.99 (1H, d), 7.14 (1H, d), 7.94(1H, d), 8.07 (1H, s); MS m/z (ES⁺) 381 (MH⁺).

EXAMPLE 15

[0199] HCl salt: δ_(H) (CD₃OD, 400 MHz) 2.56 (3H, s), 2.80 (6H, s), 3.17(2H, m), 4.35 (2H, s), 4.41 (2H, m), 6.68 (2H, m), 6.98 (1H, d), 7.13(1H, d), 7.81 (1H, d), 8.00 (1H, s); MS m/z (ES⁺) 395 (MH⁺).

[0200] Compounds of formula Ie, i.e. compounds of general formula Iwhere R¹ and R² are methyl and R⁵ is —SO₂NH₂, shown in Table 2 wereprepared according to Example 12 from the precursors indicated. TheN-methyl sulfonamides analogous to Example 13 were not isolated in thesereactions and HPLC purification was not required. TABLE 2

Example Precursor

data 16 Example 2

HCl salt: δ_(H) (CD₃OD, 400 MHz) 2.98 (6H, s), 3.41 (2H, m), 4.58 (2H,s), 6.95 (2H, m), 7.08 (1H, s), 7.25 (1H, d), 7.95 (1H, d), 8.05 (1H,s); MS m/z (ES⁺) 365 (MH⁺) 17 Example 3

HCl salt: δ_(H) (CD₃OD, 300 MHz) 2.54 (3H, s), 2.98 (6H, s), 4.53 (2H,s), 7.01 (1H, d), 7.20 (1H, dd), 7.33 (1H, s), 7.42 (1H, d), 7.99 (1H,d), 8.04 (1H, s); MS m/z (TS⁺) 387 (MH⁺) 18 Example 4

HCl salt: δ_(H) (CD₃OD, 400 MHz) 2.43 (3H, s), 2.88 (6H, s), 4.42 (2H,s), 6.99 (3H, m), 7.42 (1H, t), 7.92 (1H, d), 8.06 (1H, s); MS m/z (ES⁺)371 (MH⁺) 19 Example 6

HCl salt: δ_(H) (CD₃OD, 400 MHz) 2.89 (3H, s), 3.17 (2H, m), 4.39 (2H,m), 4.47 (2H, s), 6.78 (1H, d), 6.87 (3H, m), 7.89 (1H, d), 8.01 (1H,s); MS m/z (TS⁺) 367 (MH⁺) 20 Example 7

TFA salt: δ_(H) (CDCl₃, 400 MHz) 2.22 (6H, s), 3.60 (2H, t), 5.05 (4H,d), 6.75-6.90 (3H, m), 7.20 (1H, d), 7.60 (1H, m), 8.00 (1H, m); MS m/z349 (MH⁺) 21 Example 8

HCl salt: δ_(H) (CD₃OD, 400 MHz) 2.10 (2H, m), 2.85-3.00 (10H, m), 4.30(1H, brs), 4.50 (2H, s), 6.80-6.95 (2H, m), 7.05 (1H, s), 7.25 (1H, d),7.80 (1H, d), 8.10 (1H, s); MS m/z (ES⁺) 347 (MH⁺) 22 Example 10

HCl salt: δ_(H) (CD₃OD, 400 MHz) 2.93 (6H, s), 4.21 (4H, s), 4.50 (2H,s), 6.91 (1H, d), 7.02 (1H, d), 7.09 (1H, s), 7.37 (1H, d), 7.91 (1H,d), 8.05 (1H, s); MS m/z (TS⁺) 365 (MH⁺) 23 Example 11

HCl salt: δ_(H) (DMSO-d₆, 400 MHz) 2.76 (6H, s), 3.21 (2H, t), 3.38 (2H,t), 4.39 (2H, s), 6.80 (1H, d), 6.86 (1H, d), 7.10 (1H, s), 7.28 (3H,m), 7.80 (1H, d), 8.06 (1H, s), 10.23 (1H, br); MS m/z (TS⁺) 365 (MH⁺)

[0201]

[0202] The title compound was prepared from the secondary amine ofExample 9 by the method of Example 110; δ_(H) (CD₃OD, 400 MHz) 2.27 (3H,s), 2.41 (3H, s), 2.61 (6H, s), 4.19 (2H, s), 6.76 (1H, d), 6.88-6.93(2H, m), 7.20 (1H, d), 7.82 (1H, d), 8.03 (1H, d); MS m/z (TS⁺) 367(MH⁺).

[0203] Dimethylamine hydrochloride (424 mg, 5.2 mmol), Et₃N (725 μL, 5.2mmol), AcOH (298 μL, 5.2 mmol) and sodium triacetoxyborohydride (1.10 g,5.2 mmol) were added to a solution of the aldehyde from Preparation 24(1.00 g, 3.47 mmol) in THF (15 mL) and DCM (15 mL) and the mixture wasstirred at room temperature for 16 h. After removing the solvent invacuo the residue was taken up in 2M HCl (20 mL) and washed with ether(2×15 mL). The aqueous layer was basified with NaOH pellets andextracted with DCM (4×20 mL). The combined DCM extracts were washed withbrine, dried (MgSO₄) and evaporated. The residue was taken up in a smallamount of DCM and treated with 1M ethereal HCl to precipitate the HClsalt. This was filtered, washed with ether and dried to give a whitesolid (936 mg) contaminated with triethylamine hydrochloride. This wasdissolved in 1M NaOH (10 mL) and extracted with EtOAc (3×15 mL). Theorganic extracts were washed with brine (10 mL), dried (MgSO₄) andevaporated before being re-dissolved in EtOAc and evaporated again. Theresidue was taken up in DCM and treated with 1M ethereal HCl toprecipitate the HCl salt, which was filtered, washed with ether anddried to give a white solid (635 mg, 52%); δ_(H) (CDCl₃, 300 MHz) 2.35(3H, s), 2.45 (3H, s), 2.79 (6H, s), 3.90 (3H, s), 4.21 (2H, s), 6.70(1H, d), 6.73 (1H, s), 6.90 (2H, m), 7.18 (1H, d), 7.65 (1H, s), 12.83(1H, brs); MS m/z (TS⁺) 318 (MH⁺).

[0204] Compounds of formula If, i.e. compounds of general formula Iwhere R¹ and R² are methyl, shown in Table 3 were prepared according toExample 25 from the precursors indicated. TABLE 3

Example Precursor R⁴ R⁵

data 26 Prep 25 H F

HCl salt: δ_(H) (CDCl₃, 300 MHz) 2.23 (6H, s), 3.41 (2H, s), 6.98 (2H,m), 7.34 (2H, m), 7.48 (1H, dd), 7.98 (1H, d), 8.08 (1H, d), 8.80 (1H,s); MS m/z (TS⁺) 297 (MH⁺) 27 Prep 39 H —NO₂

δ_(H) (CDCl₃, 300 MHz) 2.32 (6H, s), 2.36 (3H, s), 2.47 (3H, s), 3.60(2H, s), 6.80 (1H, d), 6.87 (2H, d), 7.19 (1H, d), 8.03 (1H, d), 8.40(1H, d); MS m/z (ES⁺) 333 (MH⁺) 28 Prep 38 H —NO₂

Taken on crude at ˜75% purity; δ_(H)(CDCl₃, 400 MHz) 2.33 (6H, s), 3.24(2H, m), 3.38 (2H, m), 3.66 (2H, s), 6.76 (2H, m), 6.86 (1H, m), 7.17(1H, d), 8.00 (1H, dd), 8.37 (1H, d) 29 Prep 26 H H

δ_(H) (CDCl₃, 300 MHz) 2.28 (6H, s), 3.50 (2H, s), 7.03 (2H, m),7.20-7.40 (3H, m), 7.52 (2H, m), 7.98 (1H, d), 8.09 (1H, d), 8.81 (1H,m); MS m/z (TS⁺) 279 (MH⁺) 30 Prep 27 H H

HCl salt: δ_(H) (d₆-DMSO, 300 MHz) 2.77 (6H, d), 4.38 (2H, d), 7.08 (1H,d), 7.36 (1H, t), 7.52 (1H, t), 7.62 (1H, s), 7.80 (1H, d), 7.91 (1H,dd), 8.10 (1H, d), 9.25 (1H, s), 9.52 (1H, s); MS m/z (TS⁺) 280 (MH⁺) 31Prep 29 H H

Maleate salt: δ_(H) (d₆-DMSO, 300 MHz) 2.77 (6H, 5), 4.33 (2H, s), 5.98(2H, s), 6.87 (1H, d), 7.21 (1H, dt), 7.30 (1H, dd), 7.41 (1H, dt), 7.58(1H, dd), 7.88 (1H, d), 8.11 (1H, d), 9.32 (1H, 5); MS m/z 285 (MH⁺) 32Prep 33 H Br

HCl salt: δ_(H) (DMSO-d₆, 400 MHz) 2.77 (6H, d), 3.23 (3H, m). 3.39 (2H,m), 4.32 (2H, d), 6.75 (2H, m), 7.03 (1H, s), 7.26 (1H, d), 7.57 (1H,dd), 7.87 (1H, s), 10.06 (1H, br, s); MS m/z (ES⁺) 366 (MH⁺) 33 Prep 32Br H

δ_(H) (CDCl₃, 400 MHz) 2.22 (6H, s), 2.30 (3H, s), 2.41 (3H, s), 3.41(2H, s), 6.76 (2H, m), 6.94 (1H, s), 7.18 (1H, s), 7.21 (1H, obs), 7.30(1H, d); MS m/z (TS⁺) 366/368 (MH⁺)

[0205]

[0206] Chlorosulfonic acid (106 μL, 1.6 mmol) was added to a solution ofExample 29 (50 mg, 0.16 mmol) in DCM (2 mL) and the mixture was stirredfor 3 h at room temperature. Water (2 mL) was added, the mixture wasadjusted to pH 6 with sat aq NaHCO₃ and extracted with DCM (2×5 mL). Theorganic extracts were dried (MgSO₄) and filtered and 8M methylamine inEtOH (0.3 mL) was added. After standing for 1 h the solvent was removedin vacuo and the residue was purified by column chromatography [SiO₂;95:5:0.5 (DCM/MeOH/880 NH₃)]. The product was taken up in EtOAc andconverted to the HCl salt by the addition of ethereal HCl. This gave thedesired product as a hygroscopic solid (3 mg, 5%); δ_(H) (CD₃OD, 300MHz)2.60 (3H, s), 2.99 (6H, s), 4.60 (2H, s), 7.21 (1H, d), 7.96 (1H, d),8.04 (3H, m), 8.19 (1H, s), 8.38 (1H, d), 9.03 (1H, d), 9.18 (1H, d); MSm/z (TS⁺) 371 (MH⁺).

[0207] Trifluoroacetic anhydride (0.96 mL, 6.8 mmol) was added to asolution of the amine of Example 48 (900 mg, 3.4 mmol) and triethylamine(1.9 mL, 13.6 mmol) in CH₂Cl₂ (15 mL) at 0° C. and the mixture wasstirred for 5 min. The solvent was removed in vacuo and the residue waspartitioned between CH₂Cl₂ and water. The organic layer was washed withbrine, dried (MgSO₄) and evaporated to give a yellow oil, which was usedwithout further purification. This crude oil was taken up in CH₂Cl₂ (20mL), cooled to 0° C. and ClSO₃H (2.4 mL, 36.1 mmol) was added dropwise.The mixture was allowed to warm to room temperature and stirred for 4 hbefore being poured into ice water. The mixture was extracted withCH₂Cl₂ (50 mL) and the organic layer was treated with a saturatedsolution of NH₃ in MeOH (10 mL). After stirring for 4 h 1M LiOH (20 mL)was added and stirring was continued overnight. Tlc analysis indicatedreaction was incomplete so further 1M LiOH (50 mL) was added and themixture was stirred for 2 h. The mixture was acidified to pH 8 with 2MHCl and extracted with CH₂Cl₂ (3×200 mL). The combined organic extractswere dried (MgSO₄) and evaporated and the residue was triturated withether to give the title compound (500 mg, 43%) as a yellow solid; δ_(H)(CDCl₃, 400 MHz) 2.46 (3H, s), 3.87 (2H, s), 6.93 (1H, d), 7.25 (1H, s),7.39 (1H, t), 7.42 (1H, d), 7.78 (1H, d), 8.00-8.08 (2H, m), 8.12 (1H,d), 8.86 (1H, s); MS m/z (ES⁺) 344 (MH⁺).

[0208] The aldehyde of Preparation 19 (1.10 g, 3.28 mmol) was dissolvedin 8M methylamine in EtOH (4.1 mL, 32.8 mmol) and stirred for 5 h beforethe portionwise addition of NaBH₄ (372 mg, 9.83 mmol) over 30 min. EtOH(100 mL) was added and the reaction was stirred for 16 h before beingconcentrated in vacuo. The residue was quenched with 6M HCl until pH 1and the precipitated HCl salt was collected by filtration, washed withwater (100 mL) and dried in vacuo to give a crystalline solid (1.04 g,82%); δ_(H) (CDCl₃, 400 MHz) 2.62 (3H, s), 3.26 (2H, t), 3.41 (2H, t),4.18 (2H, s), 6.66 (1H, d), 6.90 (1H, d), 7.03 (1H, s), 7.19 (1H, d),7.39 (1H, d), 7.80 (1H, s); MS m/z (ES⁺) 350, 352 (MH⁺).

[0209] Compounds of formula Ig, i.e. compounds of general formula Iwhere R¹ and R⁴ are hydrogen and R² is methyl, shown in Table 4 wereprepared according to Example 36 from the precursors indicated. Forthose compounds which were isolated as the free base the reactionmixture was partitioned between 2M HCl and ether after removal of thereaction solvent in vacuo. The aqueous layer was then basified andextracted with DCM, the DCM layer being dried (MgSO₄) and evaporated togive the desired secondary amine. TABLE 4

Example Precursor R⁵

data 37 Prep 20 Br

HCl salt: δ_(H) (d₆-DMSO, 300 MHz) 2.48 (3H, s), 2.59 (3H, s), 4.18 (2H,s), 6.88 (1H, d), 7.01 (1H, d), 7.16 (1H, d), 7.45 (1H, t), 7.59 (1H,d), 7.91 (1H, s); MS m/z (TS⁺) 356, 358 (MH⁺) 38 Prep 21 Br

δ_(H) (CDCl₃, 400 MHz) 2.43 (3H, s), 3.11 (2H, t), 3.78 (2H, s), 4.41(2H, t), 6.44 (1H, s), 6.51 (1H, d), 6.77 (1H, d), 6.98 (1H, d), 7.31(1H, d), 7.55 (1H, s); MS m/z (ES⁺) 366, 368 (MH⁺) 39 Prep 22 Br

δ_(H) (CDCl₃, 400 MHz) 2.41 (3H, s), 2.45 (3H, s), 3.72 (2H, s), 6.77(1H d), 6.85 (1H, d), 6.99 (1H, s), 7.18 (1H, d), 7.36 (1H, d), 7.59(1H, s); MS m/z (TS⁺) 372, 374 (MH⁺) 40 Prep 38 —NO₂

δ_(H) (CDCl₃, 300 MHz) 2.55 (3H, s), 3.30 (2H, m), 3.43 (2H, m), 3.95(2H, s), 6.80 (2H, m), 6.91 (1H, s), 7.22 (1H, d), 8.05 (1H, d), 8.40(1H, s); MS m/z (ES⁺) 317 (MH⁺) 41 Prep 36 —NO₂

δ_(H) (CDCl₃, 400 MHz) 2.45 (3H, S), 3.10 (2H, m), 3.86 (2H, s), 4.40(2H, m), 6.53 (2H, m), 6.80 (1H, d), 7.01 (1H, d), 8.00 (1H, d), 8.27(1H, s); MS m/z (TS⁺) 333 (MH⁺) 42 Prep 40 —NO₂

δ_(H) (CDCl₃, 400 MHz) 2.14 (2H, m), 2.52 (3H, s), 2.93 (4H, t), 3.92(2H, s), 6.78 (1H, d), 6.81 (1H, d), 6.91 (1H, s), 7.22 (1H, d), 8.02(1H, dd), 8.29 (1H, s); MS m/z (TS⁺) 299 (MH⁺) 43 Prep 24 —OMe

HCl salt: δ_(H) (CDCl₃, 300 MHz) 2.35 (3H, s), 2.45 (3H, s), 2.60 (3H,s), 3.84 (3H, s), 4.17 (2H, s), 6.80 (1H, d), 6.82 (1H, s), 6.88 (2H,s), 7.15 (1H, d), 7.42 (1H, s), 9.85 (2H, brs); MS m/z (TS⁺) 304 (MH⁺)44 Prep 23 Br

δ_(H) (CDCl₃, 300 MHz) 2.35 (3H, s), 2.45 (6H, s), 3.77 (2H, s), 6.73(2H, m), 6.80 (1H, s), 7.19 (1H, d), 7.32 (1H, d), 7.57 (1H, s); MS m/z(TS⁺) 352, 354 (MH⁺) 45 Prep 30 H

HCl salt: δ_(H) (d₆- DMSO, 400 MHz) 2.22 (3H, s), 2.42 (3H, s), 2.58(3H, s), 4.18 (2H, s), 6.78 (1H, d), 6.96 (1H, d), 6.99 (1H, s), 7.18(1H, t), 7.25 (1H, d), 7.38 (1H, t), 7.60 (1H, d); MS m/z (ES⁺) 274(MH⁺) 46 Prep 31 H

HCl salt: δ_(H) (CDCl₃, 400 MHz) 2.55 (3H, brs), 3.21 (2H, t), 3.32 (2H,m), 4.17 (2H, s), 6.76 (1H, d), 6.84 (1H, d), 6.99 (1H, s), 7.04 (1H,m), 7.12 (1H, d), 7.28 (1H, obs), 7.61 (1H, d); MS m/z (ES⁺) 272 (MH⁺)47 Prep 28 H

Maleate salt: δ_(H) (DMSO-d₆, 400 MHz) 2.60 (3H, s), 4.19 (2H, s), 5.99(2H, s), 7.03 (1H, d), 7.29 (1H, m), 7.37 (1H, s), 7.45 (3H, m), 7.60(1H, d), 8.06 (1H, d), 8.37 (1H, d), 8.74 (2H, br), 8.83 (1H, dd); MSm/z 264 (MH⁺) 48 Prep 26 H

δ_(H) (CDCl₃, 300 MHz) 2.64 (3H, s), 4.25 (2H, s), 6.89 (1H, d), 7.19(1H, t), 7.30-7.41 (2H, m), 7.45 (1H, s), 7.49 (1H, d), 7.69 (1H, d),8.08 (1H, d), 8.16 (1H, d), 8.87 (1H, d); MS m/z (ES⁺) 529 (2M + H⁺) 49Prep 34 —CN

HCl salt: δ_(H) (CD₃OD, 400 MHz) 2.81 (3H, s), 3.30 (1H, br), 4.42 (2H,s), 7.17 (1H, br), 7.82 (1H, br), 8.06 (1H, br), 8.11 (3H, br), 8.39(1H, br), 9.18 (1H, br), 9.21 (1H, br); MS m/z (ES⁺) 290 (MH⁺)

[0210]

[0211] A mixture of the bromide of Example 32 (400 mg, 1.10 mmol),acrylamide (156 mg, 2.19 mmol), triethylamine (0.38 mL, 2.74 mmol),palladium 11 acetate (12.5 mg, 0.06 mmol) and tri-o-tolylphosphine (33.4mg, 0.11 mmol) in acetonitrile (15 mL) was heated at reflux for 72 h.After cooling to room temperature the solvent was removed in vacuo andthe residue was partitioned between EtOAc (50 mL) and 2M HCl (50 mL).The aqueous phase was basified with 2M NaOH and extracted with EtOAc(3×50 mL). The combined basic extracts were dried (MgSO₄) andevaporated. The residue was purified by column chromatography [SiO₂;96:4:0.5 (DCM/MeOH/880 NH₃) increasing polarity to 90:10:1] to give thetitle compound (196 mg, 50%) as a beige foam; δ_(H) (CDCl₃, 400 MHz)2.28 (6H, s), 3.24 (2H, t), 3.38 (2H, t), 3.51 (2H, s), 5.73 (2H, br),6.42 (1H, d), 6.69 (1H, dd), 6.82 (2H, m), 7.10 (1H, d), 7.32 (1H, d),7.60 (1H, d), 7.69 (1H, s); MS m/z (ES⁺) 355 (MH⁺).

[0212] A solution of Sml₂ in THF (0.1 M, 21.9 mL, 2.19 mmol) was addedto a solution of the alkene of Example 50 (194 mg, 0.55 mmol) in THF (5mL) under nitrogen followed by water (1 mL). After stirring at roomtemperature for 10 min the reaction was quenched with 6M NaOH (10 mL)and stirred for 30 min. The organic phase was separated and the aqueousphase was extracted with EtOAc (2×20 mL). The combined organic layerswere dried (MgSO₄) and evaporated to an oil, which was purified bycolumn chromatography [SiO₂; 93:7:1 (DCM/MeOH/880 NH₃) increasingpolarity to 90:10:1] to give the title compound (90 mg, 46%); δ_(H)(CDCl₃, 400 MHz) 2.25 (6H, s), 2.54 (2H, t), 2.97 (2H, t), 3.22 (2H, t),3.36 (2H, t), 3.42 (2H, s), 5.20-5.46 (2H, br), 6.54 (1H, d), 6.73 (1H,s), 6.81 (1H, d), 7.05 (2H, m), 7.31 (1H, s); MS m/z (TS⁺) 357 (MH⁺).

[0213] Compounds of formula If, i.e. compounds of general formula Iwhere R¹ and R² are methyl, shown in Table 5 were prepared according toPreparation 50 from the precursors indicated. TABLE 5

Example Precursor R⁴ R⁵

data 52 Example 32 H —CO₂Me

δ_(H) (CDCl₃, 400 MHz) 2.29 (6H, s), 3.26 (3H, m), 3.39 (2H, m), 3.54(2H, s), 3.89 (3H, s), 6.62 (1H, d), 6.84 (2H, m) 7.13 (1H, d), 7.86(1H, d), 8.12 (1H, s); MS m/z (TS⁺) 344 (MH⁺) 53 Example 33 —CO₂Me H

δ_(H) (CDCl₃, 400 MHz) 2.24 (6H, s), 2.33 (3H, s), 2.42 (3H, s), 3.48(2H, s), 3.82 (3H, s), 6.73 (2H, m), 7.14 (1H, d), 7.50 (1H, s), 7.55(1H, d), 7.78 (1H, d); MS m/z (TS⁺) 346 (MH⁺)

[0214] Compounds of formula If, i.e. compounds of general formula Iwhere R¹ and R² are methyl, shown in Table 6 were prepared according toPreparation 55 from the precursors indicated. TABLE 6 Example PrecursorR⁴ R⁵

data 54 Example 52 H —CO₂H

δ_(H) (CD₃OD, 400 MHz) 2.95 (6H, s), 3.29 (2H, m), 3.42 (2H, m), 4.52(2H, s), 6.80 (1H, d), 6.89 (1H, d), 7.03 (1H, s), 7.29 (1H, d), 8.06(1H, d), 8.23 (1H, s); MS m/z (TS⁺) 330 (MH⁺) 55 (˜80% purity) Example55 —CO₂H H

δ_(H) (CD₃OD, 400 MHz) 2.27 (3S, s), 2.42 (3H, s), 2.88 (6H, s), 4.43(2H, s), 6.95 (2H, m), 7.26 (1H, m), 7.42 (2H, m), 7.72 (1H, m)

[0215] Compounds of formula If, i.e. compounds of general formula Iwhere R¹ and R² are methyl, shown in Table 7 were prepared according toPreparation 59 from the precursors indicated. TABLE 7 Example PrecursorR⁴ R⁵

data 56 Example 54 H —CONH₂

δ_(H) (CDCl₃, 400 MHz) 2.27 (6H, s), 3.25 (2H, m), 3.38 (2H, m), 3.54(2H, s), 5.90-6.38 (2H, br), 6.59 (1H, d), 6.80 (1H, s), 6.86 (1H, d),7.11 (1H, d), 7.71 (1H, d), 7.92 (1H, s); MS m/z (TS⁺) 329 (MH⁺) 57Example 55 —CONH₂ H

HCl salt: δ_(H) (CD₃OD, 400 MHz) 2.32 (3H, s), 2.43 (3H, s), 2.94 (6H,s), 4.47 (2H, s), 6.98 (2H, br), 7.27 (1H, br), 7.36 (1H, br), 7.62 (1H,br); MS m/z (TS⁺) 331 (MH⁺)

[0216] Compounds of formula If, i.e. compounds of general formula Iwhere R¹ and R² are methyl, shown in Table 8 were prepared according toPreparation 69 from the precursors indicated TABLE 8 Example PrecursorR⁴ R⁵

data 58 Example 52 H —CH₂OH

HCl salt: δ_(H) (DMSO-d₆, 400 MHz) 2.76 (6H, s), 3.22 (2H, m), 3.40 (2H,m), 4.30 (2H, s), 4.49 (2H, s), 5.27 (1H, br, s), 6.68 (1H, d), 6.83(1H, d), 6.97 (1H, s), 7.25 (1H, d), 7.37 (1H, d), 7.60 (1H, s), 10.07(1H, br); MS m/z (TS⁺) 316 (MH⁺) 59 Example 53 —CH₂OH H

HCl salt: δ_(H) (CD₃OD, 400 MHz) 2.34 (3H, s), 2.46 (3H, s), 2.90 (6H,s), 4.40 (2H, s), 4.55 (2H, s), 6.89 (1H, s), 6.95 (2H, m), 7.18 (1H,d), 7.28 (1H, d), 7.50 (1H, d); MS m/z (TS⁺) 318 (MH⁺)

[0217]

[0218] The protected amine of Preparation 59 (317 mg, 0.76 mmol) wasdissolved in a saturated solution of HCl in DCM (25 mL) at 0° C. andleft for 1 h before being neutralised by the addition of 10% aq K₂CO₃(25 mL). Water (50 mL) was added and the layers were separated. Theaqueous layer was extracted with DCM (25 mL) and the combined organiclayers were dried (MgSO₄) and evaporated. The resulting oil wasdissolved in EtOAc (10 mL) and treated with 1M ethereal HCl (1 mL). Thewhite precipitate was collected by filtration and dried in vacuo to givethe desired product (211 mg, 77%); δ_(H) (CD₃OD, 400 MHz) 2.77 (3H, s),3.35 (2H, obs), 3.39 (2H, t), 4.34 (2H, s), 6.79 (1H, d), 6.90 (1H, dd),7.02 (1H, s), 7.21 (1H, d), 7.83 (1H, d), 8.00 (1H, s); MS m/z (TS⁺) 315(MH⁺).

[0219] Compounds of formula Ig, i.e. compounds of general formula Iwhere R¹ and R⁴ are hydrogen and R² is methyl, shown in Table 9 wereprepared according to Example 60 from the precursors indicated. TABLE 9

Ex Prec R⁵

data 61 Prep 61

HCl salt: δ_(H) (CDCl₃, 400 MHz) 2.77 (3H, d), 3.35 (2H, obs), 3.36 (3H,s), 3.39 (2H, t), 3.51 (4H, s), 4.35 (2H, s), 6.80 (1H, d), 6.90 (1H,dd), 7.01 (1H, s), 7.21 (1H, d), 7.79 (1H, d), 7.96 (1H, s); MS m/z(TS⁺) 373 (MH⁺) 62 Prep 60

HCl salt: δ_(H) (CD₃OD, 400 MHz) 2.77 (3H, s), 2.88 (3H, s), 3.35 (2H,obs), 3.39 (2H, t), 4.35 (2H, s), 6.79 (1H, d), 6.90 (1H, dd), 7.01 (1H,s), 7.20 (1H, d), 7.78 (1H, d), 7.96 (1H, s); MS m/z (TS⁺) 329 (MH⁺) 63Prep 62

HCl salt: δ_(H) (d₆-DMSO, 300 MHz) 2.52 (3H, obs), 2.61 (3H, s), 4.21(3H, s), 6.90 (1H, d), 7.07 (1H, d), 7.19 (1H, d), 7.40 (1H, brs), 7.48(1H, t), 7.92 (1H, d), 7.96 (1H, s), 8.21 (1H, s); MS m/z (TS⁺) 321(MNH₄ ⁺) 64 Prep 63

HCl salt: δ_(H) (d₆-DMSO, 300 MHz) 2.52 (3H, obs), 2.60 (3H, s), 2.79(3H, d), 4.21 (2H, s), 6.89 (1H, d), 7.07 (1H, d), 7.19 (1H, d), 7.48(1H, t), 7.85 (1H, d), 8.19 (1H, s), 8.48 (1H, d); MS m/z (TS⁺) 335(MH⁺) 65 Prep 64

HCl salt: δ_(H) (d₆-DMSO, 300 MHz) 2.52 (3H, obs), 2.60 (3H, s), 3.27(3H, s), 3.46 (4H, m), 4.22 (2H, s), 6.91 (1H, d), 7.08 (1H, d), 7.20(1H, d), 7.50 (1H, t), 7.89 (1H, d), 8.10 (1H, s), 8.58 (1H, brs); MSm/z (TS⁺) 379 (MH⁺) 66 Prep 65

HCl salt: δ_(H) (d₆-DMSO, 300 MHz) 2.52 (3H, obs), 2.60 (3H, t), 4.11(2H, s + H₂O), 6.82 (1H, d), 7.21 (1H, d), 7.40 (3H, s + d), 7.88 (1H,d), 7.96 (1H, brs), 8.21 (1H, s); MS m/z (ES⁺) 337 (MH⁺) 67 Prep 66

HCl salt: δ_(H) (d₆-DMSO, 300 MHz) 2.52 (3H, obs), 2.60 (3H, t), 2.79(3H, d), 4.22 (2H, t), 6.94 (1H, d), 7.22 (1H, d), 7.40 (2H, s + d),7.83 (1H, d), 8.19 (1H, d), 8.46 (1H, d; MS m/z (ES⁺) 351 (MH⁺) 68 Prep67

δ_(H) (CDCl₃, 400 MHz) 2.41 (3H, s), 3.08 (2H, m), 3.80 (2H, s), 4.37(2H, m), 5.94-6.36 (2H, brd), 6.46 (1H, s), 6.49 (1H, d), 6.81 (1H, d),6.96 (1H, d), 7.65 (1H, d), 7.86 (1 H, s); MS m/z (TS⁺) 331 (MH⁺) 69Prep 68

HCl salt: δ_(H) (CDCl₃, 400 MHz) 2.42 (3H, s), 3.08 (2H, m), 3.44-3.50(4H, m), 3.80 (2H, s), 4.40 (2H, m), 6.45 (1H, s), 6.49 (1H, d), 6.62(1H, brs), 6.83 (1H, d), 6.96 (1H, d), 7.62 (1H, d), 7.78 (1H, s); MSm/z (TS⁺) 390 (MH⁺) 70 Prep 70

HCl salt: δ_(H) (d₆-DMSO, 300 MHz) 2.48 (3H, s), 2.58 (3H, s), 4.12 (2H,s),4.50 (2H, d), 5.32 (1H, t), 6.92 (2H, m), 7.03 (1H, dd), 7.39 (1H,dd), 7.46 (1H, d), 7.60 (1H, s); MS m/z (TS⁺) 308 (MH⁺) 71 Prep 69

HCl salt: δ_(H) (d₆-DMSO, 300 MHz) 2,52 (3H, obs), 2.58 (3H, t), 4.10(2H, s + H₂O), 4.48 (2H, s), 6.94 (1H, d), 7.11 (1H, d), 7.21 (1H, s),7.25 (2H, m), 7.57 (1H, s); MS m/z (ES⁺) 324 (MH⁺) 72 Prep 49 —C≡N

HCl salt: δ_(H) (d₆-DMSO, 300 MHz) 2.52 (3H, s), 2.60 (3H, s), 4.24 (2H,s), 6.94 (1H, d), 7.04 (1H, d), 7.28 (1H, d), 7.50 (1H, t), 7.86 (1H,d), 8.08 (1H, s); MS m/z (TS⁺) 303 (MH⁺) 73 Prep 73

HCl salt: δ_(H) (CDCl₃, 300 MHz) 2.48 (3H, s), 2.64 (3H, s), 2.99 (3H,s), 4.23 (2H, s), 4.30 (2H, d), 6.40 (1H, br), 6.81-6.89 (3H, m),7.26-7.35 (2H, obs), 7.92 (1H, s); MS m/z (ES⁺) 385 (MH⁺), (ES⁻) 383 (M− H⁺) 74 Prep 71

HCl salt: δ_(H) (CD₃OD, 400 MHz) 2.30 (3H, s), 2.44 (3H, s), 2.73 (3H,s), 4.25 (2H, s), 4.59 (2H, s), 6.81 (1H, d), 6.88-6.92 (2H, m), 7.24(1H, d), 7.37 (1H, d), 7.46 (1H, s); MS m/z (ES⁺) 304 (MH⁺) 75 Prep 72

HCl salt: δ_(H) (CD₃OD, 300 MHz) 2.37 (3H, s), 2.48 (3H, s), 2.78 (3H,s), 2.96 (3H, s), 4.27 (2H, s), 4.31 (2H, s), 6.85 (1H, d), 6.92-7.00(2H, m), & .31 (1H, d), 7.41 (1H, d), 7.57 (1H, s); MS m/z (ES⁺) 381(MH⁺), (ES⁻) 379 (M − H⁺) 76 Prep 75

HCl salt: δ_(H) (CD₃OD, 400 MHz) 2.29 (3H, s), 2.41 (3H, s), 2.43 (3H,s), 3.76 (2H, s), 4.30 (2H, s), 6.72-6.79 (3H, m), 7.12 (1H, br), 7.27(2H, obs); MS m/z (ES⁺) 435 (MH⁺), (ES⁻) 433 (M − H⁺)

EXAMPLE 77N-{4-[(Dimethylamino)methyl]-3-[3-methyl-4-(methylsulfanyl)phenoxy]benzyl}methanesulfonamide

[0220]

[0221] Example 77 was prepared from the Boc protected sulfonamide ofPreparation 74 by the method of Example 60; HCl salt: δ_(H) (CD₃OD, 400MHz) 2.29 (3H, s), 2.42 (3H, s), 2.82 (3H, s), 2.89 (6H, s), 4.17 (2H,s), 4.39 (2H, s), 6.39 (3H, m), 7.19 (1H, d), 7.48 (1H, d); MS m/z (TS⁺)395 (MH⁺).

[0222] Zn(CN)₂ (700 mg, 5.96 mmol) and Pd(PPh₃)₄ (1.97 g, 1.7 mmol) wereadded to a solution of the bromide of Example 44 (3.0 g, 8.52 mmol) inDMF (20 mL) and the mixture was heated at 100° C. for 17 h. The reactionwas cooled to room temperature, diluted with water (100 mL) andextracted with ether (2×100 mL then 3×50 mL). The combined organiclayers were washed with water (3×50 mL), dried (MgSO₄) and evaporated toa yellow oil. Initial purification by column chromatography [SiO₂;95:5:0.5 (DCM/MeOH/880 NH₃)] was unsuccessful so the material wasre-chromatographed [SiO₂; 50% pentane in 95:5:0.5 (DCM/MeOH/880 NH₃)increasing polarity to 0% pentane] to give the product (1.275 g, 50%) asa pale yellow oil. A sample was taken up in DCM (5 mL) and treated with1M ethereal HCl to give the HCl salt as a white powder which wascollected by filtration; δ_(H) (CDCl₃, 300 MHz) 2.35 (3H, s), 2.47 (6H,s), 3.88 (2H, s), 6.79 (1H, d), 6.87 (2H, m), 7.20 (1H, d), 7.46 (1H,d), 7.72 (1H, s); MS m/z (TS⁺) 299 (MH⁺).

[0223] A mixture of the nitrile of Example 78 (404 mg, 1.35 mmol) andKOH (304 mg, 5.42 mmol) in tert-butanol (10 mL) was heated at reflux for1 h under N₂. After cooling to room temperature the solvent was removedin vacuo and the residue was partitioned between water (10 mL) and DCM(10 mL). The aqueous layer was extracted with DCM (4×20 mL) and thecombined organic layers were washed with brine, dried (MgSO₄) andevaporated. The residue was purified by column chromatography [SiO₂;93:7:1 (DCM/MeOH/880 NH₃)] to give the desired product (376 mg, 88%) asa white foam; δ_(H) (CDCl₃, 300 MHz) 2.35 (3H, s), 2.47 (3H, s), 2.49(3H, s), 3.88 (2H, s), 5.90-6.30 (2H, brs), 6.82 (3H, m), 7.19 (1H, d),7.70 (1H, d), 7.90 (1H, s); MS m/z (TS⁺) 317 (MH⁺).

[0224] Compounds of formula Ih, i.e. compounds of general formula Iwhere R¹ and R² are methyl and R⁴ is hydrogen, shown in Table 10 whereprepared according to Example 12 from the precursors indicated. TABLE 10

Example Precursor R⁵

data 80 Example 60

δ_(H) (CD₃OD, 400 MHz) 2.91 (6H, s), 3.35 (2H, obs), 3.38 (2H, t), 4.45(2H, s), 6.81 (1H, d), 6.90 (1H, d), 7.03 (1H, s), 7.21 (1H, d), 7.86(1H, d), 8.03 (1H, s); MS m/z (TS⁺) 329 (MH⁺) 81 Example 62

δ_(H) (CD₃OD, 400 MHz) 2.90-2.99 (9H, m), 3.35 (2H, obs), 3.43 (2H, t),4.50 (2H, s), 6.88 (1H, d), 6.97 (1H, d), 7.07 (1H, s), 7.28 (1H, d),7.85 (1H, d), 8.03 (1H, s); MS m/z (TS⁺) 343 (MH⁺) 82 Example 61

δ_(H) (CDCl₃, 400 MHz) 2.90 (6H, brm), 3.35 (2H, obs), 3.37 (2H, brm),3.51 (4H, brm), 4.43 (2H, brs), 6.80-6.94 (2H, brd), 7.01 (1H, brs),7.20 (1H, brs), 7.82 (1H, brs), 7.98 (1H, brs); MS m/z (TS⁺) 387 (MH⁺)83 Example 63

δ_(H) (CDCl₃, 300 MHz) 2.29 (6H, s), 2.47 (3H, s), 3.51 (2H, s), 6.73(2H, s), 6.97 (1H, d), 7.30 (1H, t), 7.79 (1H, d), 7.97 (1H, s); MS m/z(TS⁺) 335 (MNH₄ ⁺) 84 Example 64

δ_(H) (CDCl₃, 300 MHz) 2.29 (6H, s), 2.46 (3H, s), 3.02 (3H, d), 3.54(2H, s), 6.20 (1H, brs), 6.69 (2H, m), 6.97 (1H, d), 7.30 (1H, t), 7.75(1H, d), 7.91 (1H, s); MS m/z (TS⁺) 349 (MH⁺) 85 Example 65

HCl salt: δ_(H) (CDCl₃, 300 MHz) 2.49 (3H, s), 2.94 (6H, s), 3.42 (3H,s), 3.65 (4H, m), 4.33 (2H, s), 6.79 (2H, d), 6.96 (1H, d), 7.35 (1H,t), 7.39 (1H, brs), 7.98 (1H, d), 8.68 (1H, s); MS m/z (TS⁺) 393 (MH⁺)86 Example 66

δ_(H) (CDCl₃, 400 MHz) 2.38 (6H, s), 2, 47 (3H, s), 3.53 (2H, s), 6.88(2H, d), 7.03 (1H, s), 7.19 (1H, d), 7.77 (1H, d), 7.95 (1H, s); MS m/z(ES⁺) 351 (MH⁺) 87 Example 67

δ_(H) (CDCl₃, 400 MHz) 2.27 (6H, s), 2.46 (3H, s), 3.01 (3H, d), 3.50(2H, s), 6.19 (1H, brs), 6.88 (2H, m), 7.00 (1H, s), 7.19 (1H, d), 7.72(1H, d), 7.85 (1H, s); MS m/z (ES⁺) 365 (MH⁺) 88 Example 68

HCl salt: δ_(H) (CDCl₃, 400 MHz) 2.25 (6H, s), 3.07 (2H, s), 3.49 (2H,s), 4.37 (2H, m), 5.47-6.22 (2H, brd), 6.44 (1H, s), 6.49 (1H, d), 6.86(1H, d), 6.95 (1H, d), 7.68 (1H, d), 7.87 (1H, s); MS m/z (TS⁺) 346(MH⁺) 89 Example 69

HCl salt: δ_(H) (CD₃OD, 400 MHz) 2.91 (6H, s), 3.13 (2H, s), 3.27 (3H,s), 4.39 (2H, s), 4.46 (2H, s), 6.64 (2H, s + d), 6.87 (1H, d), 7.08(1H, d), 7.95 (1H, d), 8.00 (1H, s); MS m/z (TS⁺) 403 (MH⁺) 90 Example70

HCl salt: δ_(H) (d₆-DMSO, 300 MHz) 2.46 (3H, s), 2.74 (6H, s), 4.29 (2H,s), 4.51 (2H, s), 5.32 (1H, brs), 6.93 (2H, d), 7.08 (1H, d), 7.41 (2H,m), 7.63 (1H, 5); MS m/z (TS⁺) 322 (MH⁺) 91 Example 71

HCl salt: δ_(H) (d₆-DMSO, 400 MHz) 2.52 (3H, obs), 2.76 (6H, s), 4.09(2H, s), 4.49 (2H, s), 5.32 (1H, brs), 6.87 (1H, d), 7.08 (1H, d), 7.26(1H, s), 7.38 (2H, m), 7.60 (1H, s); MS m/z (ES⁺) 338 (MH⁺) 92 Example78 —C≡N

HCl salt: δ_(H) (CDCl₃, 400 MHz) 2.35 (3H, s), 2.48 (3H, s), 2.87 (6H,d), 4.39 (2H, d), 6.85 (1H, d), 6.90 (1H, d), 6.93 (1H, dd), 7.21 (1H,d), 7.60 (1H, d), 8.17 (1H, s); MS m/z (TS⁺) 313 (MH⁺) 93 Example 72—C≡N

HCl salt: δ_(H) (d₆-DMSO, 300 MHz) 2.49 (3H, obs), 2.79 (6H, s), 4.41(2H, s), 6.97 (1H, d), 7.14 (1H, d), 7.32 (1H, d), 7.49 (1H, t), 7.87(1H, d), 8.22 (1H, s); MS m/z (TS⁺) 317 (MH⁺) 94 Example 45 H

HCl salt: δ_(H) (d₆-DMSO, 400 MHz) 2.23 (3H, s), 2.42 (3H, s), 2.76 (6H,s), 4.34 (2H, s), 6.80 (1H, d), 7.97 (1H, dd), 7.00 (1H, s), 7.19 (1H,t), 7.24 (1H, d), 7.40 (1H, t), 7.67 (1H, d); MS m/z (ES⁺) 288 (MH⁺) 95Example 46 H

HCl salt: δ_(H) (CDCl₃, 400 MHz) 2.74 (6H, s), 3.22 (2H, m), 3.38 (2H,m), 4.26 (2H, s), 6.71 (1H, d), 6.80 (2H, brm), 7.15 (2H, brm), 7.32(1H, d), 7.79 (2H, d); MS m/z (ES⁺) 286 (MH⁺) 96 Example 73

HCl salt: δ_(H) (CD₃OD, 300 MHz) 2.46 (3H, s), 3.93 (6H, s), 3.97 (3H,s), 4.24 (2H, s), 4.42 (2H, s), 6.91-7.00 (3H, m), 7.41-7.54 (2H, m),7.61 (1H, s); MS m/z (TS⁺) 399 (MH⁺), (ES⁻) 397 (M − H⁺) 97 Example 75

HCl salt: δ_(H) (CD₃OD, 400 MHz) 2.31 (3H, s), 2.43 (3H, s), 2.86-2.94(9H, m), 4.22 (2H, s), 4.39 (2H, s), 6.83 (1H, d) 6.89-6.94 (2H, m),7.26 (1H, d), 7.40 (1H, d), 7.54 (1H, s); MS m/z (ES⁻) 393 (M − H⁺) 98Example 74

HCl salt: δ_(H) (CD₃OD, 300 MHz) 2.36 (3H, s), 2.47 (3H, s), 2.98 (6H,s), 4.43 (2H, s), 4.63 (2H, s), 6.89 (1H, d), 6.91-7.00 (2H, m), 7.30(1H, d), 7.43 (1H, d), 7.55 (1H, s); MS m/z (ES⁺) 318 (MH⁺) 99 Example76

HCl salt: δ_(H) (CD₃OD, 300 MHz) 2.39 (3H, s), 2.47 (3H, s), 2.85 (6H,s), 4.32 (2H, s), 4.44 (2H, s), 6.80-6.86 (3H, m), 7.21 (1H, d), 7.35(1H, d), 8.08 (1H, s); MS m/z (ES⁺) 449 (MH⁺), (ES⁻) 447 (M − H⁺) 100Example 102

δ_(H) (CD₃OD, 400 MHz) 2.26 (6H, s), 3.58 (2H, s), 6.97 (1H, d), 7.35(1H, d), 7.46 (1H, dd), 7.54 (1H, d), 7.80 (1H, d), 8.03 (2H, m), 8.20(1H, d), 8.74 (1H, d); MS m/z (TS⁺) 322 (MH⁺)

[0225] Example 94 was Also Prepared as Follows

[0226] A solution of the product from Preparation 30 (200 g, 0.78 mol)in DCM (1.4 L) was added to THF (1.4 L). To this mixture was addeddimethylamine hydrochloride (69.5 g, 0.85 mol) and triethylamine (235 g,2.33 mol) successively. The temperature was adjusted to 20° C. and after3 h sodium triacetoxyborohydride (246 g, 1.16 mol) was added (After 20h, if the reaction has completed, continue with work up; otherwise seenote below). Dichloromethane (2 L) was added and a solution of 8% sodiumbicarbonate (0.9 L) was added over 0.5 h. The layers were separated andthe organic layer washed with water (1 L). The layers were againseparated and the organic layer was concentrated. Ethyl acetate (0.27 L)was added and the solvent removed replacing with fresh ethyl acetate(800 ml). The solution was then cooled to below 5° C. and 7.02 M HCl/IPA(0.117 L, 0.82 mol) added whist the temperature was maintained below 10°C. After stirring for 1 h at below 5° C., the slurry was filtered,washed with ethyl acetate (3×0.2 L) and dried in a vacuum oven at 50° C.overnight to give the desired product as a powdery solid (141.5 g, 56%).[Note: if reaction hasn't completed after 20 h. Add another portion ofdimethylamine hydrochloride (13 g, 0.16 mol) and triethylamine (43.4 g,0.43 mol) successively. After 2 h at room temperature add sodiumtriacetoxyborohydride (46 g, 0.22 mol). Leave for a further 20 h andthen work up as above].

[0227] Compounds of formula Ii, i.e. compounds of general formula Iwhere R² is methyl, R⁴ is hydrogen and R⁵ is —C(═O)NH₂, shown in Table11 were prepared according to Example 79 form the precursors indicated.TABLE 11

Example Precursor R¹

data 101 Example 92 Me

δ_(H) (CDCl₃, 300 MHz) 2.30 (6H, s), 2.35 (3H, s), 2.46 (3H, s), 3.58(2H, s), 5.60-5.80 (1H, brs), 6.00-6.20 (1H, brs), 6.32 (3H, m), 7.19(1H, m), 7.71 (1H, d), 7.90 (1H, s); MS m/z (TS⁺) 331 (MH⁺) 102 Example49 H

δ_(H) (CDCl₃, 400 MHz) 2.43 (3H, s), 3.84 (2H, s), 6.94 (1H, d), 7.20(1H, d), 7.34-7.39 (1H, m), 7.43 (1H, dd), 7.70 (1H, d), 7.91 (1H, s),7.99 (1H, d), 8.09 (1H, d), 8.82 (1H, d); MS m/z (ES⁺) 309 (MH⁺)

[0228]

[0229] A mixture of the nitro compound of Example 27 (2.0 g, 6 mmol), Fepowder (2.51 g, 44.9 mmol) and CaCl₂ (300 mg, 2.7 mmol) in EtOH (20 mL)and water (4 mL) was heated at reflux for 20 h. After cooling to roomtemperature the solvent was removed in vacuo and the residue waspartitioned between brine (100 mL) and ether (100 mL). The aqueous layerwas extracted with ether (50 mL) and the combined organic layers weredried (MgSO₄) and evaporated to give the product (1.47 g, 81%) as anorange oil; δ_(H) (CDCl₃, 300 MHz) 2.22 (6H, s), 2.32 (3H, s), 2.40 (3H,s), 3.33 (2H, s), 6.59 (1H, dd), 6.60-6.75 (2H, m), 6.78 (1H, dd), 6.94(1H, s), 7.10-7.20 (3H, m); MS m/z (ES⁺) 303 (MH⁺).

[0230] The title compound was prepared from the nitro compound ofExample 28 by the method of Example 103; δ_(H) (CDCl₃, 400 MHz) 2.20(6H, s), 3.16 (2H, t), 3.30 (4H, m), 3.54 (2H, br), 6.53 (1H, dd), 6.60(1H, d), 6.71 (2H, m), 6.79 (1H, d), 7.01 (1H, d); MS m/z (ES⁺) 301(MH⁺).

EXAMPLE 105N-[3-(Aminomethyl)-4-(2,3-dihydro-1,4-benzoxathiin-6-yloxy)phenyl]-methanesulfonamide

[0231]

[0232] The nitrile of Preparation 95 (720 mg, 1.99 mmol) was dissolvedin a 1M solution of BH₃.THF in THF (10 mL, 10 mmol) and the mixture washeated at reflux for 3 h. After cooling to room temperature the reactionwas quenched by the cautious addition of MeOH (10 mL). The solvent wasevaporated, the residue was treated with 6M HCl (10 mL) and heated atreflux for 1 h. After cooling, the mixture was basified with 2M NaOH andthe pH was adjusted to 7 with sat aq NH₄Cl. The mixture was extractedwith EtOAc (3×50 mL) and DCM (2×50 mL) and the combined organic layerswere dried (MgSO₄) and evaporated to give a beige foam (685 mg, 94%)which was used without further purification; δ_(H) (CDCl₃, 400 MHz) 3.00(3H, s), 3.13 (2H, m), 3.87 (2H, s), 4.40 (2H, m), 6.62 (1H, d), 6.67(1H, s), 6.79 (2H, d), 7.08 (1H, d), 7.25 (1H, d); MS m/z (TS⁺) 367(MH⁺).

[0233] Compounds of formula Ij, i.e. compounds of general formula Iwhere R¹, R² and R⁴ are hydrogen and R⁵ is —NR⁸—SO₂Me, shown in Table 12were prepared according to Example 105 from the precursors indicatedTABLE 12

Example Precursor

R⁸ data 106 Prep 96

H δ_(H) (CDCl₃, 300 MHz) 2.47 (3H, s), 3.02 (3H, s), 3.08 (3H, br), 3.85(2H, s), 6.87 (2H, m), 6.99 (1H, d), 7.15 (1H, dd), 7.20 (1H, d), 7.30(1H, d); MS m/z (ES⁻) 371 (M − H⁺) 107 Prep 97

H Used crude in a subsequent step: δ_(H) (CD₃OD, 400 MHz) 2.37 (3H, s),2.95 (3H, s), 3.75 (2H, s), 6.58 (1H, d), 6.71 (2H, m), 6.89 (1H, d),7.15 (1H, dd), 7.28 (1H, obs) 108 Prep 100

Me Used crude in a subsequent step: δ_(H) (CDCl₃, 300 MHz) 2.36 (3H, s),2.46 3H, s), 2.90 (3H, s), 3.36 (3H, s), 3.93 (2H, s), 6.83 (3H, m),7.20 (2H, m), 7.42 (1H, d). 109 Prep 99

H δ_(H) (CD₃OD, 400 MHz) 2.24 (3H, s), 2.40 (3H, s), 2.97 (3H, s), 3.80(2H, s), 6.60 (1H, d), 6.81-6.87 (2H, m), 7.08-7.17 (2H, m), 7.29 (1H,d); MS m/z (ES⁺) 353 (MH⁺), (ES⁻) 351 (M − H⁺)

EXAMPLE 110N-{4-(2,3-Dihydro-1,4-benzoxathiin-6-yloxy)-3-[(methylamino)methyl]phenyl}-methanesulfonamide

[0234]

[0235] Dicyclohexylcarbodiimide (460 mg, 2.23 mmol) was added to asolution of pentafluorophenol (413 mg, 2.24 mmol) in ether (10 mL)followed by formic acid (95 μL, 2.5 mmol). The mixture was stirred for 2h and then filtered, washing the residue with ether. The filtrate wasconcentrated to ˜5 mL and a solution of the primary amine of Example 105(411 mg, 1.1 mmol) in DCM (10 mL) was added. The mixture was stirred for16 h then concentrated to an oily residue. This crude oil was taken upin a solution of BH₃.THF in THF (1M, 20 mL, 20 mmol) and heated atreflux for 1.5 h under N₂. After cooling to room temperature thereaction was quenched by the cautious addition of MeOH (10 mL) and thenconcentrated in vacuo. The oily residue was treated with 6M HCl andheated at reflux for 30 min. After cooling to room temperature themixture was basified with aq K₂CO₃ and extracted with DCM (3×). Thecombined organic extracts were dried (MgSO₄) and evaporated. The residuewas purified by column chromatography [SiO₂; 90:10:1 (DCM/MeOH/880 NH₃)]to give a colourless oil which was taken up in EtOAc (20 mL) and treatedwith 1M ethereal HCl (2 mL). After stirring for 1.5 h the solid wascollected by filtration to give the title product (282 mg, 60%); δ_(H)(CD₃OD, 400 MHz) 2.78 (3H, s), 2.98 (3H, s), 3.18 (2H, m), 4.29 (2H, s),4.39 )2H, m), 6.74 (1H, d), 6.80-6.90 (3H, m), 7.22 (1H, d), 7.44 (1H,s); MS m/z (TS⁺) 381 (MH⁺).

[0236] Compounds of formula Ik, i.e. compounds of general formula Iwhere R¹ and R⁴ are hydrogen, R² is methyl and R⁵ is —NHSO₂Me, shown inTable 13 were prepared according to Example 110 from the precursorsindicated. TABLE 13

Example Precursor

data 111 Example 107

δ_(H) (CDCl₃, 400 MHz) 2.40 (6H, s), 2.99 (3H, s), 3.70 (2H, s), 6.64(2H, t), 6.88 (1H, d), 7.15 (1H, d), 7.25 (2H, s); MS m/z (TS⁺) 371(MH⁺) 112 Example 106

HCl salt: δ_(H) (CD₃OD, 400 MHz) 2.55 (3H, s), 3.82 (3H, s), 3.04 (3H,s), 4.32 (2H, s), 6.97 (1H, d), 7.11 (1H, d), 7.23 (1H, s), 7.30 (1H,d), 7.39 (1H, d), 7.56 (1H, s); MS m/z (TS⁺) 387 (MH⁺) 113 Example 109

HCl salt: δ_(H) (CD₃OD, 400 MHz) 2.24 (3H, s), 2.39 (3H, s), 2.76 (3H,s), 2.93 (3H, s), 4.25 (2H, s), 6.69 (1H, d), 6.82 (1H, d), 6.93 (1H,s), 7.17 (1H, d), 7.21 (1H, d), 7.43 (1H, s); MS m/z (ES⁺) 367 (MH⁺),(ES⁻) 365 (M − H⁺)

[0237] Compounds of formula Im, i.e. compounds of general formula Iwhere R¹ and R⁴ are hydrogen, R² is methyl and R⁵ is —NR⁸SO₂Me, shown inTable 14 were prepared according to Example 110 from the precursorsindicated. TABLE 14

Example Precursor R⁸

data 114 Prep 85 H

HCl salt: δ_(H) (CDCl₃, 400 MHz) 2.09 (2H, m), 2.73 (3H, s), 2.88 (4H,t), 3.00 (3H, s), 4.21 (2H, s), 6.80 (2H, m), 6.88 (1H, s), 7.19 (1H,d), 7.34 (1H, d), 7.75 (1H, s); MS m/z (TS⁺) 347 (MH⁺) 115 Prep 84 H

HCl salt: δ_(H) (d₆-DMSO, 400 MHz) 2.20 (3H, s), 2.40 (3H, s), 2.55 (3H,s), 2.97 (3H, s), 4.08 (2H, s), 6.80 (1H, d), 6.87 (1H, d), 6.91 (1H,s), 7.14 (1H, d), 7.20 (1H, d), 7.39 (1H, s); MS m/z (TS⁺) 367 (MH⁺) 116^(a) Prep 88 Me

δ_(H) (CDCl₃, 300 MHz) 2.17 (3H, s), 2, 37 (3H, s), 2.48 (3H, s), 2.62(3H, s), 2.97 (3H, s), 3.34 (3H, s), 4.23 (2H, s), 6.79 (1H, d), 6.94(2H, s), 7.35 (2H, m), 7.81 (1H, s); MS m/z (TS⁺) 381 (MH⁺) 117 Prep 89

HCl salt: δ_(H) (CDCl₃, 400 MHz) 2.29 (3H, s), 2.39 (3H, s), 2.42 (3H,s), 2.94 (3H, s), 3.60 (2H, t), 3.74 (2H, t), 3.79 (2H, s), 6.78 (3H,m), 7.14 (2H, m), 7.41 (1H, s); MS m/z (TS⁺) 410 (MH⁺) 118 Prep 87 H

δ_(H) (CDCl₃, 400 MHz) 2.42 (3H, s), 2.58-2.79 (2H, br), 2.94 (3H, s),3.08 (2H, m), 3.71 (2H, s), 4.38 (2H, m), 6.39 (1H, s), 6.47 (1H, d),6.82 (1H, d), 6.94 (1H, d), 7.07 (1H, d), 7.18 (1H, s); MS m/z (TS⁺) 381(MH⁺) 119 Prep 86 H

δ_(H) (CD₃OD, 400 MHz) 2.80 (3H, s), 3.00 (3H, s), 3.27 (2H, m), 3.40(2H, m), 4.28 (2H, m), 6.85 (2H, m), 7.00 (1H, s), 7.20 (1H, d), 7.24(1H, dd), 7.47 (1H, d); MS m/z (TS⁺) 365 (MH⁺)

[0238] Compounds of formula In, i.e. compounds of general formula Iwhere R¹ and R² are methyl, R⁴ is hydrogen, and R⁵ is —NR⁸SO₂Me, shownin Table 15 were prepared according to Example 12 from the precursorsindicated. TABLE 15

Example Precursor R⁸

Data 120 Example 111 H

HCl salt: δ_(H) (CD₃OD, 400 MHz) 2.42 (3H, s), 2.89 (6H, s), 2.98 (3H,s), 4.37 (2H, s), 6.88 (2H, m), 6.97 (1H, d), 7.28 (1H, d), 7.39 (1H,t), 7.48 (1H, s); MS m/z (TS⁺) 385 (MH⁺) 121 (from primary amine)Example 105 H

δ_(H) (CDCl₃, 400 MHz) 3.00 (3H, s), 3.13 (2H, m), 3.87 (2H, s), 4.40(2H, m), 6.62 (1H, d), 6.67 (1H, s), 6.79 (2H, d), 7.08 (1H, d), 7.25(1H, d); MS m/z (TS⁺) 367 (MH⁺) 122 (from primary amine) Example 106 H

HCl salt: δ_(H) (CD₃OD, 400 MHz) 2.49 (3H, s), 2.93 (6H, s), 3.00 (3H,s), 4.41 (2H, s), 6.95 (1H, d), 7.07 (1H, d), 7.21 (1H, s), 7.33 (2H,m), 7.54 (1H, s); MS m/z (TS⁺) 395 (MH⁺) 123 Example 114 H

HCl salt: δ_(H) (CDCl₃, 400 MHz) 2.12 (2H, m), 2.81 (6H, s), 2.91 (4H,t), 3.13 (3H, s), 4.25 (2H, s), 6.73 (1H, d), 6.83 (2H, m), 7.10 (1H,d), 7.39 (1H, d), 7.90 (1H, s); MS m/z (TS⁺) 360 (MH⁺) 124 Example 118 H

δ_(H) (CDCl₃, 400 MHz) 2.22 (6H, s), 2.98 (3H, s), 3.07 (2H, m), 3.41(2H, s), 4.38 (2H, m), 6.36 (1H, s), 6.45 (1H, d), 6.86 (1H, d), 6.92(1H, d), 7.12 (1H, d), 7.27 (1H, s); MS m/z (TS⁺) 395 (MH⁺) 125 Example117

HCl salt: δ_(H) (CDCl₃, 300 MHz) 2.38 (3H, s), 2.48 (3H, s), 2.86 (6H,brs), 3.15 (3H, s), 3.73 (2H, brs), 3.87 (2H, brs), 4.35 (2H, brs), 6.82(3H, brs), 7.20 (2H, m), 7.41 (1H, d); MS m/z (TS⁺) 425 (MH⁺) 126 (fromprimary amine) Example 108 Me

HCl salt: δ_(H) (CD₃OD, 400 MHz) 2.29 (3H, s), 2.43 (3H, s), 2.89 (3H,s), 2.91 (6H, s), 3.26 (3H, s), 4.42 (2H, s), 6.84 (1H, d), 6.97 (2H,m), 7.27 (1H, d), 7.47 (1H, dd), 7.60 (1H, d); MS m/z (TS⁺) 395 (MH⁺)127 (from primary amine) Example 109 H

HCl salt: δ_(H) (CD₃OD, 400 MHz) 2.27 (3H, s), 2.42 (3H, s), 2.94 (6H,s), 2.99 (3H, s), 4.42 (2H, s), 6.77 (1H, d), 6.89 (1H, d), 6.99 (1H,s), 7.19 (1H, d), 7.28 (1H, dd), 7.50 (1H, s); MS m/z (TS⁺) 381 (MH⁺),(ES⁺) 381 (MH⁺), (ES⁻) 379 (M − H⁺)

EXAMPLE 128N-{3-[(Dimethylamino)methyl]-4-[3-methyl-4-(methylsulfanyl)phenoxy]-phenyl}methanesulfonamide

[0239]

[0240] Methanesulfonyl chloride (371 μL, 4.79 mmol) was added to asolution of the aniline of Example 103 (725 mg, 2.4 mmol) and Et₃N (1mL, 7.17 mmol) in DCM (10 mL) at 0° C. After stirring at 0° C. for 1 hthe reaction was allowed to warm to room temperature before the solventwas removed in vacuo. 2M NaOH (10 mL) was added to the residue and themixture was stirred overnight. The resulting clear solution wasneutralised by the addition of sat aq NH₄Cl and extracted with DCM (2×30mL). The combined organic layers were dried (MgSO₄) and evaporated togive an oil. This was taken up in EtOAc (10 mL), the HCl salt wasprecipitated by the addition of 1M ethereal HCl and the product (669 mg,67%) was collected by filtration; δ_(H) (d₆-DMSO, 400 MHz) 2.23 (3H, s),2.42 (3H, s), 2.75 (6H, s), 3.04 (3H, s), 4.38 (2H, s), 6.84 (1H, d),6.93 (1H, d), 6.98 (1H, s), 7.17-7.25 (2H, m), 7.50 (1H, s); MS m/z(ES⁺) 381 (MH⁺).

[0241] Compounds of formula Ip, i.e. compounds of general formula Iwhere R¹ and R² are methyl, R⁴ is hydrogen, and R⁵ is —NHSO₂R⁹, shown inTable 16 were prepared according to Example 128 from the precursorsindicated. TABLE 16

Example Precursor R⁹

data 129 Example 104 Me

HCl salt: δ_(H) (CD₃OD, 400 MHz) 2.92 (6H, s), 2.99 (3H, s), 3.26 (2H,t), 3.40 (2H, t), 4.41 (2H, s), 6.88 (2H, d), 7.00 (1H, s), 7.10 (1H,d), 7.27 (1H, d), 7.50 (1H, s); MS m/z (TS⁺) 381 (MH⁺) 130 Example 103Et

HCl salt: δ_(H) (d₆-DMSO, 400 MHz) 1.21 (3H, t), 2.23 (3H, s), 2.42 (3H,s), 2.74 (6H, s), 3.16 (2H, q), 4.26 (2H, s), 6.92 (1H, d), 6.92 (1H,d), 6.98 (1H, s), 7.18-7.25 (2H, m), 7.51 (1H, s); MS m/z (ES⁺) 395(MH⁺)

[0242]

[0243] To a solution of 5-(aminosulfonyl)-2-fluorobenzoic acid [preparedaccording to Chem. Pharm. Bull. 1995, 43, 582-7] (22.98 g, 105 mmol) inTHF (500 mL) at room temperature under nitrogen was addedcarbonyldiimidazole (17 g, 105 mmol). After stirring for 2.25 h asolution of methylamine in THF (2M, 70 mL, 140 mmol) was added dropwiseand the reaction was allowed to stir for 18 h. The crude reactionmixture was concentrated to a low volume and EtOAc (150 mL) was added tothe resulting thick oil. This mixture was stirred and a granularprecipitate formed which was collected by filtration. This crudeproduct, contaminated with imidazole, was suspended in DCM (300 mL) andheated at reflux for 5 h. After cooling to room temperature the mixturewas filtered to give the desired product (19.8 g, 81%) containing <2%w/w imidazole; ¹H NMR δ_(H) (300 MHz, d₄-MeOH) 2.97 (3H, s), 7.40 (1H,t), 8.05 (1H, m), 8.29 (1H, d); MS m/z (TS⁺) 250 (MNH₄ ⁺).

[0244] (i) Preparation of 2-chloro-1-(methylsulfanyl)-4-nitrobenzene

[0245] To a solution of 4-fluoro-3-chloronitrobenzene (27 g, 156 mmol)in DMF (150 mL) at room temperature was added5-tert-butyl-4-hydroxy-2-methylphenyl sulfide (100 mg) followed bysodium thiomethoxide (NaSMe) (10 g, 143 mmol) and the reaction wasstirred for 6 h. The DMF was removed in vacuo and the residue waspartitioned between ether (1 L) and water (1 L). The ether layer waswashed with water (1 L) and brine (1 L), dried (MgSO₄) and the solventwas removed under reduced pressure. The residue was purified by columnchromatography (SiO₂; DCM: pentane 1:5 increasing polarity to 3:7) togive the title compound (15.22 g, 49%) as a yellow solid; δ_(H) (400MHz, CDCl₃) 2.53 (3H, s), 7.20 (1H, d), 8.09 (1H, dd), 8.20 (1H, d).

[0246] (ii) Preparation of 3-chloro-4-(methylsulfanyl)aniline

[0247] To a mixture of the above compound (14.08 g, 69 mmol) in aceticacid (300 mL) and water (60 mL) was added Fe powder (23 g, 412 mmol) andthe reaction mixture was swirled until all the starting material haddissolved. The mixture was left to stand for 1.5 h and the acetic acidwas then removed under reduced pressure. The residue was taken up in satNaHCO₃ (aq) (500 mL) and EtOAc (500 mL) and filtered through Arbocel®.The layers were separated, the aqueous phase was extracted with EtOAc(300 mL) and the combined organics were washed with brine, dried (MgSO₄)and the solvent was removed in vacuo to give the title compound (11.52g, 96%) as a beige solid; δ_(H) (400 MHz, CDCl₃) 2.38 (3H, s), 3.66 (2H,br), 6.53 (1H, dd), 6.70 (1H, d), 7.12 (1H, d); MS m/z (ES⁺) 174 (MH⁺).

[0248] (iii) Preparation of 3-chloro-4-(methylsulfanyl)phenol

[0249] The above aniline (11.5 g, 66.2 mmol) was dissolved in theminimum THF (˜15 mL) and water (500 mL) was added with vigorousstirring, followed by conc H₂SO₄ (25 mL). The mixture was cooled in anice-water bath and a solution of NaNO₂ (5.0 g, 72.5 mmol) in iced water(10 mL), was added via pipette under the surface of the reactionmixture. The reaction was stirred at 0° C. for 1.5 h and the resultingyellow/brown solution was decanted from the remaining solid into adropping funnel containing ice (˜200 g). This solution was added at asteady rate over 7 min to a vigorously stirred mixture of Cu(NO₃)₂ (230g, 0.99 mol) and Cu₂O (8.52 g, 67.4 mmol) in water (1 L) at roomtemperature. After the addition was complete the mixture was stirred fora further 15 min before being extracted with ether (500 mL). Theresidual red/brown solid in the reaction flask was taken up in MeOH (100mL) and diluted with ether (300 mL) before being poured into the aqueouslayer from above. The ether layer was separated and the combined organiclayers were extracted with 1M NaOH (3×100 mL). The aqueous extracts wereacidified with conc. HCl and then extracted with ether (2×150 mL). Theether layers were then washed with brine, dried (MgSO₄) and the solventwas removed in vacuo to give the phenol (5.465 g, 47%) as a browncrystalline solid; δ_(H) (400 MHz, CDCl₃) 2.44 (3H, s), 5.08 (1H, br),6.77 (1H, d), 6.93 (1H, d), 7.18 (1H, d); MS m/z (ES⁻) 173 (M−H⁺).

[0250] This compound was prepared using a similar method to thatdescribed above for Preparation 2 starting from commercially available3,4-difluoronitrobenzene; δ_(H) (CDCl₃, 300 MHz) 2.40 (3H, s), 5.03 (1H,br), 6.60 (2H, m), 7.27 (1H, m obscured); MS m/z (ES ⁻) 157 (M−H⁺).

[0251] 1,2-Dibromoethane (2.3 mL, 26.7 mmol) and K₂CO₃ (8.21 g, 59.4mmol) were slurried in acetone (250 mL) and a solution of2-sulfanyl-1,4-benzenediol (prepared according to J. Org. Chem. 1990,55, 2736) (4.22 g, 29.7 mmol) in acetone (50 mL) was added over 4 h tothe stirred mixture. Once the addition was complete stirring wascontinued for a further 10 h before the solvent was removed in vacuo.The residue was partitioned between water (50 mL) and EtOAc (50 mL), theaqueous layer was extracted with EtOAc (50 mL) and the combined organiclayers were dried (MgSO₄) and evaporated. Purification of the residue bycolumn chromatography [SiO₂; 9:1 (pentane/EtOAc)] gave the titlecompound (2.48 g, 55%) as a pale orange oil; δ_(H) (CDCl₃, 400 MHz) 3.08(2H, m), 4.31 (2H, m), 4.44 (1H, s), 6.42 (1H, d), 6.49 (1H, s), 6.66(1H, d); MS m/z (ES⁻) 167 (M−H⁺).

[0252] The title compound was prepared in a similar manner to thecompound of Preparation 4 starting from 4-sulfanyl-1,3-benzenediol(prepared according to J. Org. Chem. 1979, 26, 4971-4973); δ_(H) (CDCl₃,400 MHz) 3.05 (2H, t), 4.37 (2H, t), 6.32 (1H, s), 6.35 (1H, d), 6.84(1H, d); MS m/z (TS⁺) 169 (MH⁺).

[0253] 1,3-Dihydro-2-benzofuran-5-amine (prepared according to U.S. Pat.No. 4,000,286) (2.7 g, 20 mmol) was dissolved in a mixture of water (300mL) and conc. H₂SO₄ (21 mL), cooled to 0° C. and NaNO₂ (1.43 g, 20.7mmol) in water (10 mL) was added over 15 min. After stirring at 0° C.for 1 h the mixture was allowed to stir at 10° C. for 30 min and ureawas added until a negative test with starch/KI paper was observed. Thesolution was then poured over 2 min into a mixture of water (180 mL) andconc. H₂SO₄ (12.6 mL) at 90° C. and stirred at this temperature for 1.5h. The hot mixture was filtered then allowed to cool to roomtemperature. The aqueous mixture was extracted with EtOAc (2×100 mL) andthe combined organic layers were dried (MgSO₄) and evaporated to givethe title phenol (974 mg, 36%) as a cream solid; δ_(H) (CDCl₃, 400 MHz)5.03 (4H, s), 6.71 (2H, m), 7.08 (1H, d).

PREPARATION 7 2,3-Dihydro-1-benzothiophen-6-ol

[0254]

[0255] (i) Preparation of 2,3-dihydro-1-benzothiophen-6-ol 1,1-dioxide

[0256] A suspension of 2,3-dihydro-1-benzothiophen-6-amine 1,1-dioxide[prepared according to J. Am. Chem. Soc. 1955, 77, 5939] (15.73 g, 85.8mmol) in water (500 mL) and conc. H₂SO₄ (35 mL) was warmed untilsolution was achieved. The mixture was cooled to 0° C. and a solution ofNaNO₂ (6.22 g, 90 mmol) in water (15 mL) was then added over 5 min. Thereaction was stirred at 0° C. for 1 h then urea was added, to removeexcess nitrite, until a negative test with starch/KI paper was obtained.The mixture was allowed to warm to room temperature then added withstirring to a mixture of conc. H₂SO₄ (55 mL) and water (750 mL) at 90°C. The reaction was re-heated to 90° C. and stirred at this temperaturefor 30 min. The hot reaction mixture was filtered through Arbocel® thenstirred at room temperature overnight. The aqueous mixture was extractedwith ether (2.5 L) and then EtOAc (5×500 mL) and the combined organiclayers were dried (MgSO4) and evaporated to give the desired phenol(12.7 g, 80%) which was used without further purification; δ_(H) (CDCl₃,400 MHz) 3.30 (2H, m), 3.50 (2H, m), 7.05 (1H, m), 7.14 (1H, s), 7.23(1H, m); MS m/z (ES⁻) 183 (M−H⁺).

[0257] (ii) Preparation of 2,3-dihydro-1-benzothiophen-6-ol

[0258] A solution of the sulfone from stage (i) (4.84 g, 26.3 mmol) intoluene (100 mL) and THF (70 mL) was added to a solution of DIBAL intoluene (1M, 100 mL, 100 mmol) and the mixture was then heated at refluxfor 16 h. After cooling to room temperature EtOH (75 mL) was addedcautiously followed by water (100 mL) with stirring. 6M HCl was added tothe resulting thick suspension and the organic layer was separated. Theaqueous layer was extracted with EtOAc (3×150 mL) and the combinedorganic layers were dried (MgSO₄) and evaporated to a beige solid.Purification by column chromatography [SiO₂; DCM/MeOH/880 NH₃(97:3:0.25) increasing polarity to (95:5:0.5)] afforded the desiredtitle phenol as a beige solid (1.85 g, 53%); δ_(H) (CD₃OD, 400 MHz) 3.13(2H, t), 3.30 (2H, m), 6.41 (1H, d), 6.60 (1H, s), 6.98 (1H, d); MS m/z(ES⁻) 151 (M−H⁺).

PREPARATION 85-(Aminosulfonyl)-2-[3-methyl-4-(methylsulfanyl)phenoxy]-N-methylbenzamide

[0259]

[0260] The fluoroamide of Preparation 1 (732 mg, 3.15 mmol) was treatedwith 4-(methylthio)-m-cresol (commercially available) (535 mg, 3.47mmol) and potassium carbonate (457 mg, 3.31 mmol) in DMF (10 mL). Themixture was heated at 100° C. for 5 hours. The solvent was removed byevaporation under reduced pressure and the residue was treated with 2MHCl (10 mL). The resulting suspension was extracted several times withdichloromethane. The combined dichloromethane layers contained asuspension and were evaporated to a solid residue. The residue wastriturated with ether (5 mL) and the remaining solid was washed withether (3×10 mL) to give an off-white solid (765 mg, 66%). δ_(H) (300MHz, d₆-DMSO) 2.28 (3H, s), 2.48 (3H, s), 2.70 (3H, d), 6.90 (1H, d)7.02 (1H, d), 7.03 (1H, s), 7.30 (1H, d), 7.35 (2H, s), 7.79 (1H, d),8.10 (1H, d), 8.30 (1H, m); MS m/z (TS⁺) 367 (MH⁺), 385 (MNH₄ ⁺).

PREPARATIONS 9-18

[0261] Compounds of formula Va, i.e. compounds of general formula Vwhere T is —C(═O)NHMe, R⁴ is hydrogen and R⁵ is —SO₂NH₂, shown in Table17 were prepared according to Preparation 8 using the sulfonamide ofPreparation 1 and the phenol indicated. TABLE 17

Preparation Precursor phenol

data 9 Synth. Commun. 1991, 21, 959-969

δ_(H) (d₆-DMSO, 400 MHz) 2.80 (3H, d), 3.20 (2H, t), 3,40 (2H, t), 6.90(1H, m), 7.05 (1H, s), 7.25 (1H, d), 7.35 (1H, s), 7.80 (1H, m), 8.10(1H, s), 8.30 (1H, brs); MS m/z (TS⁺) 365 (MH⁺) 10 Prep 5

δ_(H) (CD₃OD, 400 MHz) 2.92 (3H, s), 3.17 (2H, m), 4.41 (2H, m),6.60-6.70 (2H, m), 6.97 (1H, m/z (TS⁺) 381 (MH⁺) 11 Prep 3

δ_(H) (CD₃OD, 400 MHz) 2.43 (3H, s), 2.97 (1H, s), 6.89 (2H, m), 7.00(1H, d), 7.39 (1H, br), 7.88 (1H, brd), 8.23 (1H, s); MS m/z (ES⁺) 371(MH⁺) 12 Prep 2

δ_(H) (CD₃OD, 400 MHz) 2.85 (3H, s), 2.99 (3H, s), 6.99 (1H, d), 7.09(1H, d), 7.22 (1H, s), 7.37 (1H, d), 7.92 (1H, d), 8.28 (1H, s); MS m/z(ES⁺) 387 (MH⁺) 13 Prep 4

δ_(H) (CD₃OD, 400 MHz) 2.87 (3H, brs), 3.13 (2H, brs), 4.37 (2H, brs),6.73 (1H, brs), 6.82 (3H, m), 7.82 (1H, s), 8.28 (1H, brs); MS m/z (ES⁺)381 (MH⁺) 14 Prep 6

δ_(H) (d₆-DMSO, 400 MHz) 2.79 (3H, s), 4.98 (4H, brs), 6.92 (1H, d),7.04 (1H, d), 7.09 (1H, s), 7.37 (3H, m), 7.79 (1H, m), 8.10 (1H, s),8.30 (1H, s); MS m/z (TS⁺) 349 (MH⁺) 15 Commercial

δ_(H) (CD₃OD, 400 MHz) 2.08 (2H, m), 2.90 (7H, m), 6.84 (2H, m), 6.97(1H, s), 7.23 (1H, d), 7.81 (1H, d), 8.31 (1H, s); MS m/z (TS⁺) 347(MH⁺) 16 Tetrahedron 1982, 38, 2721 & Synthesis 1982, 475

Product used without purification 17 Prep 101

δ_(H) (CD₃OD, 400 MHz) 2.88 (3H, s), 4.20 (4H, s), 6.89 (1H, d), 6.97(1H, d), 7.01 (1H, s), 7.30 (1H, d), 7.84 (1H, d), 8.28 (1H, s); MS m/z(TS⁺) 382 (MNH₄ ⁺) 18 Prep 7

δ_(H) (DMSO-d₆, 400 MHz) 2.78 (3H, d), 3.23 (2H, m), 3.40 (2H, m), 6.75(1H, dd), 6.90 (1H, d), 7.02 (1H, s), 7.27 (1H, d), 7.34 (1H, d), 7.80(1H, d), 8.10 (1H, s), 8.26 (1H, br, d); MS m/z (ES⁻) 363 (M − H⁺)

PREPARATION 19 5-Bromo-2-(2,3-dihydro-1-benzothien-5-yloxy)benzaldehyde

[0262]

[0263] A mixture of 5-bromo-2-fluorobenzaldehyde (1.08 g, 5.32 mmol),5-hydroxy-2,3-dihydrobenzothiophene (prepared as described in Synth.Commun. 1991, 21, 959-964) (808 mg, 5.31 mmol) and K₂CO₃ (1.47 g, 10.6mmol) in DMF (5 mL) was heated at 90° C. for 16 h. After cooling to roomtemperature the mixture was partitioned between water (50 mL) and ether(50 mL), the aqueous layer being extracted with ether (50 mL). Thecombined organic extracts were washed with water (50 mL), dried (MgSO₄)and evaporated. The residue was purified by column chromatography [SiO₂;9:1 (pentane/EtOAc)], then triturated with ether, to give the product(1.1 g, 62%) as a pale yellow solid; δ_(H) (CDCl₃, 400 MHz) 3.28 (2H,t), 3.41 (2H, t), 6.78 (1H, d), 6.84 (1H, d), 6.92 (1H, s), 7.20 (1H,d), 7.58 (1H, d), 8.00 (1H, s), 10.43 (1H, s).

[0264] Compounds of general formula II shown in Table 18 were preparedaccording to Preparation 19 by reacting the phenol indicated with therequired 2-fluorobenzaldehyde.

[0265] In most cases the crude reaction product after aqueous work-upwas used directly in subsequent steps without further purification.TABLE 18

Preparation Precursor Phenol R⁴ R⁵

data 20 Prep 3 H Br

δ_(H) (CDCl₃, 300 MHz) 2.48 (3H, s), 6.81 (3H, m), 7.37 (1H, t), 7.64(1H, d), 8.06 (1H, s), 10.39 (1H, s); MS m/z (TS⁺) 358, 360 (MNH₄ ⁺) 21Prep 5 H Br

δ_(H) (CDCl₃, 400 MHz) 3.13 (2H, m), 4.42 (2H, m), 6.55 (1H, s), 6.59(1H, d), 6.81 (1H, d), 7.04 (1H, d), 7.59 (1H, d), 8.01 (1H, s), 10.40(1H, s) 22 Prep 2 H Br

δ_(H) (CDCl₃, 400 MHz) 2.43 (3H, s), 6.78 (1H, d), 6.94 (1H, d), 7.08(1H, s), 7.19 (1H, d), 7.59 (1H, d), 8.00 (1H, s) 23 commercial H Br

δ_(H) (CDCl₃, 300 MHz) 2.35 (3H, s), 2.49 (3H, s), 6.78 (1H, d), 6.90(2H, s), 7.22 (1H, d), 7.59 (1H, d), 8.05 (1H, s), 10.45 (1H, s); MS m/z(TS⁺) 356, 354 (MNH₄ ⁺) 24 commercial H MeO

δ_(H) (CDCl₃, 300 MHz) 2.35 (3H, s), 2.45 (3H, s), 3.87 (3H, s), 6.82(1H, d), 6.83 (1H, s), 6.92 (1H, d), 7.13 (1H, dd), 7.19 (1H, d), 7.40(1H, d), 10.40 (1H, s); MS m/z (TS⁺) 389 (MH⁺) 25 commercial H F

δ_(H) (CDCl₃, 300 MHz) 7.02 (1H, dd), 7.21 (1H, s), 7.30 (1H, m), 7.40(1H, m), 7.54 (1H, d), 7.66 (1H, dd), 8.01 (1H, d), 8.18 (1H, d), 8.88(1H, d), 10.43 (1H, s); MS m/z (ES⁺) 268 (MH⁺) 26 commercial H H

δ_(H) (CDCl₃, 400 MHz) 6.97 (1H, d), 7.21-7.27 (2H, m), 7.38 (1H, dd),7.49-7.58 (2H, m), 7.92-8.01 (2H, m), 8.11 (1H, d), 8.83 (1H, d), 10.50(1H, s); MS m/z (ES⁺) 272 MNa⁺), (ES⁻) 248 (M − H⁺) 27 J. Chem. Soc.1952, 4985-4993 H H

δ_(H) (CDCl₃, 300 MHz) 7.08 (1H, d), 7.36 (2H, m), 7.65 (1H, m), 7.79(1H, dd), 8.01 (1H, d), 8.13 (1H, d), 9.29 (1H, d), 10.45 (1H, s); MSm/z (TS⁺) 251 (MH⁺) 28 commercial H H

δ_(H) (CDCl₃, 400 MHz) 7.09 (1H, d), 7.28 (1H, m), 7.35 (1H, m), 7.40(1H, m), 7.50 (1H, br), 7.59 (1H, m), 7.86 (1H, dd), 7.99 (1H, dt), 8.15(1H, d), 8.86 (1H, m), 10.46 (1H, s); MS m/z 250 (MH⁺) 29 Chem. Pharm.Bull., 1978, 26, 1443 H H

δ_(H) (CDCl₃, 400 MHz) 6.91 (1H, d), 7.25 (2H, m), 7.55 (2H, m), 7.96(1H, m), 8.12 (1H, d), 8.95 (1H, s), 10.5 (1H, s); MS m/z 256 (MH⁺) 30commercial H H

δ_(H) (CDCl₃, 300 MHz) 2.35 (3H, s), 3.44 (3H, s), 6.87 (3H, m), 7.17(2H, m), 7.50 (1H, t), 7.92 (1H, dd), 10.52 (1H, s); MS m/z (TS⁺) 259(MH⁺) 31 Synth. Commun. 1991, 21, 959-964 H H

δ_(H) (CDCl₃, 400 MHz) 3.26 (2H, t), 3.39 (2H, m), 6.85 (2H, t), 6.92(1H, s), 7.18 (2H, m), 7.48 (1H, t), 7.92 (1H, d), 10.51 (1H, s); MS m/z(TS⁺) 257 (MH⁺) 32 commercial Br H

δ_(H) (CDCl₃, 400 MHz) 2.36 (3H, s), 2.44 (3H, s), 6.88 (2H, m), 6.96(1H, s), 7.18-7.25 (2H, obs), 7.77 (1H, d), 10.43 (1H, s) 33 Prep 7 H Br

δ_(H) (CDCl₃, 400 MHz) 3.27 (2H, m), 3.42 (2H, m), 6.67 (1H, d), 6.80(1H, d), 6.90 (1H, s), 71.6 (1H, d), 7.58 (1H, d), 8.01 (1H, s), 10.41(1H, s); MS m/z (TS⁺) 354 (MNH₄ ⁺)  34^(a) commercial H CN

δ_(H) (DMSO-d₆, 300 MHz) 6.26 (1H, d), 6.43 (1H, d), 7.49 (1H, d),7.65-7.71 (2H, m), 7.88 (1H, d), 8.07 (1H, d), 8.17 (1H, s), 8.73 (1H,d), 8.89 (1H, s); MS m/z (ES−) 273 (M −H), (ES⁺) 275 (MH⁺)

[0266] The product from Preparation 30 was also prepared as follows.

[0267] Potassium carbonate (334.1 g, 2.42 mol) and4-(methylthio)-m-cresol (273.4 g, 1.77 mol) were added successively toDMF (2 L). 2-Fluorobenzaldehyde (200 g, 1.61 mol) was then added to theslurry and the mixture heated in the range 100-110° C. After 48 h thereaction mixture was allowed to cool to room temperature and water (1.2L) added. The solution was cooled to below 10° C. and the pH adjusted to5 with concentrated HCl (0.37 L), keeping the temperature below 10° C.Water (0.15 L) and dichloromethane (0.9 L) were added and the mixturestirred. The layers were separated and the organic layer was washed withwater (4×0.75 L). The solvent was distilled to azeotropically remove thewater. Fresh dichloromethane was added as required. The drydichloromethane solution was then concentrated in vacuo to give thecrude product as an oil (422 g, 100%).

[0268] Compounds of formula IX shown in Table 19 were prepared accordingto Preparation 19, using either 2-chloro-5-nitrobenzaldehyde or2-chloro-5-nitrobenzonitrile with the phenol indicated. For thesereactions a shorter reaction time (ca. 2-3 h) was usually sufficient toachieve good conversion. In most cases the crude reaction product afteraqueous work-up was used directly in subsequent steps without furtherpurification. TABLE 19

Preparation Precursor W

data 35 Prep 3 —C≡N

δ_(H) (CDCl₃, 400 MHz) 2.48 (3H, s), 6.85-6.95 (3H, m), 7.28 (1H, t),8.30 (1H, d), 8.52 (1H, s) 36 Prep 5

δ_(H) (CDCl₃, 400 MHz) 3.14 (2H, d), 4.43 (2H, d), 6.62 (2H, m), 6.92(1H, d), 7.08 (1H, d), 8.27 (1H, d), 8.72 (1H, s), 10.51 (1H, s); MS m/z(TS⁺) 318 (MH⁺) 37 Prep 2 —C≡N

δ_(H) (CDCl₃, 300 MHz) 2.55 (3H, s), 6.94 (1H, d), 7.09 (1H, dd), 7.22(1H, d), 7.27 (1H, d), 8.36 (1H, dd), 8.60 (1H, d); MS m/z (TS⁺) 338(MNH₄ ⁺) 38 Synth. Commun. 1991, 21, 959-964

δ_(H) (CDCl₃, 400 MHz) 3.29 (2H, m), 3.42 (2H, m), 6.88 (2H, m), 6.96(1H, s), 7.23 (1H, d), 8.26 (1H, d), 8.75 (1H, s), 10.54 (1H, s) 39commercial

δ_(H) (CDCl₃, 400 MHz) 2.38 (3H, s), 2.50 (3H, s), 6.92 (1H, d), 6.99(2H, m), 7.24 (1H, d), 8.28 (1H, dd), 8.78 (1H, d), 10.57 (1H, s) 40commercial

δ_(H) (CDCl₃, 400 MHz) 2.18 (2H, m), 2.95 (4H, t), 6.90 (2H, m), 7.29(1H, d), 8.27 (1H, d), 8.79 (1H, s), 10.59 (1H, s); MS m/z (TS⁺) 301(MNH₄ ⁺) 41 Prep 4 —C≡N

δ_(H) (CDCl₃, 400 MHz) 3.18 (2H, t), 4.44 (2H, t), 6.76 (1H, d), 6.86(1H, s), 6.92 (2H, d), 8.32 (1H, d), 8.57 (1H, s); MS m/z (TS⁺) 332(MNH₄ ⁺) 42 commercial —C≡N

δ_(H) (CDCl₃, 400 MHz) 2.32 (3H, s), 2.47 (3H, s), 6.87 (1H, d), 6.94(2H, m), 7.21 (1H, d), 8.26 (1H, dd), 8.51 (1H, d); MS m/z (TS⁺) 318(MNH₄ ⁺) 43 Tetrahedron 1982, 38, 2721 & Synthesis 1982, 475 —C≡N

δ_(H) (CDCl₃, 400 MHz) 2.31 (3H, s), 2.41 (3H, s), 6.76 (1H, dd), 6.85(2H, m), 7.19 (1H, d), 8.24 (1H, dd), 8.53 (1H, d); MS m/z (TS⁺) 318(MNH₄ ⁺)

PREPARATION 44 tert-Butyl5-bromo-2-(2,3-dihydro-1-benzothien-5-yloxy)benzyl(methyl)carbamate

[0269]

[0270] The hydrochloride salt of Example 36 (1.04 g, 2.7 mmol) wasslurried in DCM (12 mL) and Et₃N (750 μL, 5.38 mmol) was added, followedby di-teff-butyl dicarbonate (766 mg, 3.51 mmol). After stirring at roomtemperature for 20 min the reaction was quenched by the addition of 0.2MHCl (20 mL). The well shaken mixture was separated and the aqueous layerwas extracted with DCM (10 mL). The combined organic layers were dried(MgSO₄) and evaporated to give the product (assumed quantitative yield)as a colourless oil which was used without further purification; δ_(H)(CDCl₃, 400 MHz) 1.56 (9H, s), 2.82-2.98 (3H, brd), 3.23 (2H, t), 3.40(2H, t), 4.44 (2H, brd), 6.71 (2H, d), 6.79 (1H, s), 7.12 (1H, d), 7.29(1H, d), 7.39 (1H, s).

[0271] Compounds of formula X shown in Table 20 were prepared accordingto Preparation 44 starting from the precursors indicated. TABLE 20

Preparation Precursor

data 45 Example 38

δ_(H) (CDCl₃, 400 MHz) 1.41 (9H, brs), 2.81 (3H, m), 3.07 (2H, m), 4.36(4H, m), 6.38 (1H, s), 6.43 (1H, d), 6.71 (1H, d), 6.92 (1H, d), 7.26(1H, d), 7.34 (1H, s); MS m/z (ES⁺) 468 (MH⁺) 46 Example 39

δ_(H) (CDCl₃, 400 MHz) 1.48 (9H, s), 2.41 (3H, s), 2, 82 (3H, brd), 4.39(2H, brd), 6.73 (1H, d), 6.80 (1H, d), 6.93 (1H, s), 7.04 (1H, d), 7.32(1H, d), 7.39 (1H, s); MS m/z (TS⁺) 474 (MH⁺) 47 Example 37

δ_(H) (CDCl₃, 300 MHz) 1.46 (9H, brs), 2.46 (3H, s), 2.89 (3H, brs),4.41 (2H, brs), 6.68 (2H, m), 6.82 (1H, d), 7.27 (1H, obs), 7.40 (1H,d), 7.43 (1H, s); MS m/z (TS⁺) 458 (MH⁺) 48 Example 44

δ_(H) (CDCl₃, 300 MHz) 1.45 (9H, br) 2.38 (3H, s), 2.44 (3H, s), 2.90(3H, br), 4.47 (2H, br), 6.70-6.81 (3H, m) 7.20 (1H, d), 7.24-7.58 (2H,m)

PREPARATION 49 tert-Butyl5-cyano-2-[3-fluoro-4-(methylsulfanyl)phenoxy]benzyl-(methyl)carbamate

[0272]

[0273] The title compound was prepared from the bromide of Preparation47 by the method of Example 78; δ_(H) (CDCl₃, 300 MHz) 1.48 (9H, brs),2.50 (3H, s), 2.93 (3H, brs), 4.55 (2H, brs), 6.79 (2H, m), 6.88 (1H,d), 7.35 (1H, t), 7.53 (1H, d), 7.59 (1H, s); MS m/z (TS⁺) 403 (MH⁺).

PREPARATION 50 Methyl3-{[(tert-butoxycarbonyl)(methyl)amino]methyl}-4-(2,3-dihydro-1-benzothien-5-yloxy)benzoate

[0274]

[0275] A mixture of the bromide of Preparation 44 (1.22 g, 2.7 mmol),Et₃N (1.13 mL, 8.11 mmol) and dichlorobis(triphenylphosphine)palladium(II) (190 mg, 0.27 mmol) in MeOH (14 mL) was heated at 80° C. under 100psi pressure of CO for 18 h. Analysis by tic indicated the reaction wasnot complete so a further portion of catalyst (190 mg, 0.27 mmol) wasadded and the mixture was heated at 100° C. under 100 psi pressure of COfor 24 h. The mixture was diluted with EtOAc (20 mL) and filteredthrough a pad of silica gel, eluting with excess EtOAc. The solvent wasremoved in vacuo and the residue was partitioned between EtOAc (50 mL)and a 2:1 mixture of water:880 NH₃ (50 mL). The aqueous layer wasextracted with EtOAc (25 mL) and the combined organic layers were dried(MgSO₄) and evaporated. Purification by column chromatography [SiO₂; 4:1(pentane/EtOAc)] gave the product (970 mg, 84%) as an oil; δ_(H) (CDCl₃,400 MHz) 1.42 (9H, s), 2.90 (3H, brs), 3.22 (2H, t), 3.38 (2H, t), 3.84(3H, s), 4.50 (2H, brd), 6/74 (2H, d), 6.82 (1H, s), 7.13 (1H, d), 7.82(1H, d), 7.93 (1H, brd); MS m/z (ES⁺) 430 (MH⁺).

[0276] Compounds of formula XI shown in Table 21 were prepared accordingto Preparation 50 starting from the precursors indicated. TABLE 21

Preparation Precursor

data 51 Prep 45

δ_(H) (CDCl₃, 400 MHz) 1.42 (9H, s), 2.86 (2H, m), 3.07 (2H, m), 3.85(3H, s), 4.37 (2H, m), 4.48 (2H, m), 6.48 (2H, m), 6.79 (1H, d), 6.97(1H, d), 7.83 (1H, d), 7.95 (1H, s); MS m/z (ES⁺) 446 (MH⁺) 52 Prep 46

δ_(H) (CDCl₃, 400 MHz) 1.43 (9H, brs), 2.47 (3H, s), 2.88 (3H, brd),3.90 (3H, s), 4.51 (2H, brd), 6.81 (1H, d), 6.91 (1H, d), 7.06 (1H, s),7.20 (1H, d), 7.89 (1H, d), 7.98 (1H, brd); MS m/z (TS⁺) 469 (MNH₄ ⁺) 53Prep 47

δ_(H) (CDCl₃, 300 MHz) 147 (9H, brs), 2.46 (3H, s), 2.91 (3H, brs), 3.94(3H, s), 4.52 (2H, brs), 6.78 (2H, m), 6.91 (1H, d), 7.35 (1H, m), 7.92(1H, d), 8.02 (1H, brs); MS m/z (TS⁺) 453 (MNH₄ ⁺) 54 Prep 48

δ_(H) (CDCl₃, 300 MHz) 1.44 (9H, s), 2.37 (3H, s), 2.47 (3H, s), 2.94(3H, br), 3.90 (3H, s), 4.73 (2H, br), 6.79-6.87 (3H, m), 7.20 (1H, d),7.86 (1H, d), 8.00 (1H, br); MS m/z (ES⁺) 454 (MNa⁺)

PREPARATION 553-{[(tert-Butoxycarbonyl)(methyl)amino]methyl}-4-(2,3-dihydro-1-benzothien-5-yloxy)benzoicacid

[0277]

[0278] A solution of the ester of Preparation 50 (970 mg, 2.26 mmol) inTHF (20 mL) and 1M LiOH (20 mL) was heated at reflux for 16 h. Aftercooling to room temperature the THF was removed in vacuo, the residuewas neutralised with sat aq NH₄Cl and the mixture was extracted with DCM(100 mL) and then ether (100 mL). The combined organic layers were dried(MgSO₄) and evaporated to give a white foam (960 mg) which was usedwithout further purification; δ_(H) (CDCl₃, 400 MHz) 1.30 (9H, s), 2.78(3H, brs), 3.20 (2H, brs), 3.38 (2H, t), 4.41 (2H, m), 6.62 (2H, m),6.78 (1H, m), 7.10 (1H, m) 7.84 (1H, m), 7.99 (1H, m); MS m/z (ES⁻) 414(M−H).

[0279] Compounds of formula XII shown in Table 22 were preparedaccording to Preparation 55 from the precursors indicated. TABLE 22

Preparation Precursor

data 56 Prep 51

δ_(H) (CDCl₃, 400 MHz) 1.26 (9H, s), 2.74 (3H, s), 3.02 (2H, m), 4.31(4H, m), 6.38 (2H, m), 6.64 (1H, d), 6.87 (1H, d), 7.68 (1H, brs), 7.78(1H, brs); MS m/z (ES⁻) 430 (M − H⁺) 57 Prep 52

δ_(H) (CDCl₃, 400 MHz) 1.44 (9H, brs), 2.49 (3H, s), 2.92 (3H, brd),4.57 (2H, brd), 6.82 (1H, d), 6.94 (1H, d), 7.08 (1H, s), 7.21 (1H, d),7.97 (1H, d), 8.04 (1H, brd); MS m/z (ES⁻) 436 (M − H⁺) 58 Prep 53

δ_(H) (CDCl₃, 300 MHz) 1.46 (9H, brs), 2.49 (3H, s), 2.93 (3H, brs),4.57 (2H, brs), 6.77 (2H, m), 6.92 (1H, d), 7.32 (1H, t), 7.99 (1H, d),8.08 (1H, brs); MS m/z (ES⁻) 420 (M − H⁺)

PREPARATION 59 tert-Butyl5-(aminocarbonyl)-2-(2,3-dihydro-1-benzothien-5-yloxy)benzyl-(methyl)carbamate

[0280]

[0281] Et₃N (267 μL, 1.92 mmol), HOBt.H₂O (129 mg, 0.84 mmol) and WSCDI(191 mg, 1.0 mmol) were added to a solution of the acid of Preparation55 (318 mg, 0.77 mmol) in DCM (10 mL) and the mixture was stirred for 1h before the addition of a saturated solution of NH₃ in THF (2 mL).After stirring for a further 16 h the reaction was diluted with water(50 mL), 0.2M HCl (20 mL) and DCM (25 mL). The organic layer wasseparated and the aqueous layer was extracted with DCM (25 mL). Thecombined organic layers were dried (MgSO₄) and evaporated to give awhite foam (assumed quantitative yield) which was used without furtherpurification; δ_(H) (CDCl₃, 400 MHz) 1.44 (9H, s), 2.91 (3H, br), 3.27(2H, t), 3.40 (2H, t), 4.54 (2H, br), 6.75-6.88 (1H, m) 7.18 (1H, d),7.68 (1H, d), 7.74 (1H, s).

[0282] Compounds of formula XII shown in Table 23 were preparedaccording to Preparation from the precursors indicated. TABLE 23

Preparation Precursor R⁵

data 60 Prep 55

δ_(H) (CDl₃, 400 MHz) 1.43 (9H, s), 2.83-3.00 (6H, m), 3.24 (2H, t),3.39 (2H, t), 4.51 (2H, brs), 6.70-6.85 (3H, m), 7.15 (1H, d), 7.62 (1H,d), 7.68 (1H, s) 61 Prep 55

δ_(H) (CDCl₃, 400 MHz) 1.46 (9H, s), 2.89 (3H, br), 3.24 (2H, t),3.37-3.43 (5H, m), 3.56 (2H, t), 3.63 (2H, m), 4.54 (2H, br), 6.46 (1H,br), 6.75-6.86 (3H, m), 7.16 (1H, d), 7.62 (1H, d), 7.69 (1H, s) 62 Prep58

δ_(H) (d₆-DMSO, 400 MHz) 1.29 (9H, br), 2.40 (3H, s), 2.75 (3H, s), 4.39(2H, s), 6.78 (1H, d), 6.91 (2H, m), 7.23 (1H, br), 7.36 (1H, t), 7.78(2H, m), 7.90 (1H, br); MS m/z (TS⁺) 438 (MNH₄ ⁺) 63 Prep 58

δ_(H) (CDCl₃, 400 MHz) 1.41 (9H, s), 2.40 (3H, s), 2.92 (3H, brs), 2.98(3H, d), 4.45 (2H, brs), 6.10 (1H, brs), 6.67 (2H, m), 6.88 (1H, d),7.27 (1H, obs), 7.63 (2H, m); MS m/z (TS⁺) 452 (MNH₄ ⁺) 64 Prep 58

δ_(H) (CDCl₃, 400 MHz) 1.40 (9H, s), 2.40 (3H, s), 2.81 (3H, brs), 3.35(3H, s), 3.53 (2H, m), 3.61 (2H, m), 4.44 (2H, brs), 6.45 (1H, brs),6.66 (2H, m), 6.87 (1H, d), 7.29 (1H, d), 7.64 (1H, d), 7.72 (1H, s); MSm/z (TS⁺) 479 (MH⁺) 65 Prep 57

δ_(H) (CDCl₃, 400 MHz) 1.43 (9H, brs), 2.47 (3H, s), 2.90 (3H, brd),4.52 (2H, brs), 6.87 (1H, d), 6.91 (1H, d), 7.03 (1H, s), 7.10 (1H, d),7.72 (1H, d), 7.78 (1H, s); MS m/z (ES⁺) 435 (M − H⁺) 66 Prep 57

δ_(H) (CDCl₃, 400 MHz) 1.42 (9H, brs), 2.47 (3H, s), 2.88 (3H, brd),3.00 (3H, d), 4.48 (2H, brs), 6.16 (1H, brd), 6.85 (2H, m), 7.01 (1H,s), 7.19 (1H, d), 7.67 (2H, m); MS m/z (ES⁻) 449 (M − H⁺) 67 Prep 56

δ_(H) (CDCl₃, 400 MHz) 1.42 (9H, s), 2.86 (3H, m), 3.08 (2H, m), 3.97(2H, m), 4.48 (2H, brs), 5.86-6.27 (2H, brs), 6.45 (1H, s), 6.49 (1H,d), 6.82 (1H, d), 6.96 (1H, d), 7.64 (1H, d), 7.71 (1H, s); MS m/z (TS⁺)331 (MH⁺ − Boc) 68 Prep 56

δ_(H) (CDCl₃, 400 MHz) 1.26 (9H, s), 2.74 (3H, s), 3.02 (2H, m), 4.31(4H, m), 6.38 (2H, m), 6.64 (1H, d), 6.87 (1H, d), 7.68 (1H, brs), 7.78(1H, brs); MS m/z (ES⁻) 430 M − H⁺)

PREPARATION 69 tert-Butyl2-[3-chloro-4-(methylsulfanyl)phenoxy]-5-(hydroxymethyl)benzyl-(methyl)carbamate

[0283]

[0284] A solution of LiAIH₄ in THF (1M, 2 mL, 2 mmol) was added dropwiseto a solution of the ester of Preparation 52 (452 mg, 1 mmol) in THF (10mL) under N₂. Once the reaction was judged complete by tic analysis,ether (10 mL) was added and the excess LiAIH₄ was quenched by thecautious addition of 2M NaOH. The organic layer was separated, washedwith brine, dried (MgSO₄) and evaporated. Purification of the residue bycolumn chromatography [SiO₂; 39:1 (DCM/MeOH)] gave the desired alcohol(200 mg, 47%) as a gummy white solid; δ_(H) (CDCl₃, 400 MHz) 1.41 (9H,brs), 1.80 (1H, brs), 2.43 (3H, s), 2.81 (3H, brd), 4.42 (2H, brd), 4.66(2H, s), 6.82 (1H, d), 6.88 (1H, d), 6.96 (1H, s), 7.16 (1H, d), 7.27(2H, obs); MS m/z (ES⁺) 446 (MNa⁺).

[0285] Compounds of formula XIV shown in Table 24 were preparedaccording to Preparation 69 starting from the precursors indicated.TABLE 24

Preparation Precursor

data 70 Prep 53

δ_(H) (CDCl₃, 400 MHz) 1.39 (9H, brs), 1.99 (1H, brs), 2.39 (3H, s),2.78 (3H, brd), 4.39 (2H, brs), 4.62 (2H, d), 6.61 (2H, t), 6.88 (1H,d), 7.20-7.30 (3H, m + CHCl₃); MS m/z (TS⁺) 408 (MH⁺) 71 Prep 54

δ_(H) (CDCl₃, 300 MHz) 1.45 (9H, s), 2.34 (3H, s), 2.46 (3H, s), 2.90(3H, br), 4.49 (2H, s), 4.67 (2H, s), 6.72-6.81 (2H, m), 6.85 (1H, d),7.18 (1H, d), 7.21-7.30 (2H, obs); MS m/z (TS⁺) 404 (MH⁺)

PREPARATION 72 tert-Butyl3-{[(tert-butoxycarbonyl)(methyl)amino]methyl}-4-[3-methyl-4-(methylsulfanyl)phenoxy]benzyl(methylsulfonyl)carbamate

[0286]

[0287] A solution of diethyl azodicarboxylate (505 μL, 3.21 mmol) in THF(5 mL) was added dropwise to a solution of tert-butylmethylsulfonylcarbamate (synthesised according to Tetrahedron Lett.1994, 35, 379-380) (655 mg, 3.36 mmol), the alcohol of Preparation 71(1.226 g, 3.04 mmol) and triphenylphosphine (880 mg, 3.36 mmol) in THF(15 mL) at 0° C. The reaction was stirred at 0° C. for 2 h then dilutedwith EtOAc (80 mL) and washed with 10% aq. K₂CO₃ (100 mL). The organiclayer was washed with brine, dried (MgSO₄) and evaporated. The residuewas purified by column chromatography [SiO₂; 1:4 EtOAc:pentane] to givethe title compound (1.406 g, 80%) as a colourless oil; δ_(H) (CDCl₃, 300MHz) 1.45 (9H, s), 1.52 (9H, s), 2.38 (3H, s), 2.44 (3H, s), 2.83 (3H,s) 3.22 (1H, s), 4.49 (2H, s), 4.85 (2H, s), 6.74-6.83 (3H, m),7.18-7.29 (3H, obs); MS m/z (TS⁺) 81 (MH⁺−BOC).

PREPARATION 73 tert-Butyl3-{[(tert-butoxycarbonyl)(methyl)amino]methyl}-4-[3-fluoro-4-(methylsulfanyl)phenoxy]benzyl(methylsulfonyl)carbamate

[0288]

[0289] The title compound was prepared from the alcohol of Preparation70 by the method of Preparation 72; δ_(H) (CDCl₃, 300 MHz) 1.44 (9H, s),1.52 (9H, s), 2.44 (3H, s), 2.82 (3H, s), 3.23 (3H, s), 4.45 (2H, s),4.87 (2H, s), 6.61-6.70 (2H, m), 6.90 (1H, d), 7.25-7.33 (3H, m); MS m/z(ES⁺) 607 (MNa⁺).

PREPARATION 74 tert-Butyl4-[(dimethylamino)methyl]-3-[3-methyl-4-(methylsulfanyl)phenoxy]benzyl(methylsulfonyl)carbamate

[0290]

[0291] The title compound was prepared from the alcohol of Example 59 bythe method of Preparation 72. The crude product was not purified bycolumn chromatography but taken on directly to the next step; δ_(H)(CDCl₃, 400 MHz) 1.39 (9H, s), 2.22 (6H, s), 2.28 (3H, s), 2.38 (3H, s),3.07 (3H, s), 3.42 (2H, s), 4.76 (2H, s), 6.72 (2H, m), 6.79 1H, s),7.07 (1H, d), 7.12 (1H, d), 7.40 (1H, obs).

PREPARATION 75 tert-Butylmethyl[2-[3-methyl-4-(methylsulfanyl)phenoxy]-5-({[(trifluoromethyl)sulfonyl]amino}methyl)benzyl]carbamate

[0292]

[0293] The title compound was prepared from the alcohol of Preparation71 by the method of Preparation 72 using trifluoromethanesulfonamideinstead of tert-butyl methylsulfonylcarbamate. The desired product wascontaminated with tert-butyl5-({{3-{[(tert-butoxycarbonyl)(methyl)amino](methyl}-4-[3-methyl-4-(methylsulfanyl)phenoxy]benzyl}[(trifluoromethyl)sulfonyl]amino}methyl)-2-[3-methyl-4-(methylsulfanyl)phenoxy]benzyl(methyl)carbamateand was taken on as a mixture; MS m/z (ES⁻) 533 (M−H⁺).

[0294] Compounds of formula XV shown in Table 25 were prepared accordingto Preparation 44 using the precursors indicated. TABLE 25

Preparation Precursor

data 76 Example 41

δ_(H) (CDCl₃, 400 MHz) (major rotamer) 1.51 (9H, s), 2.92 (3H, s), 3.10(2H, m), 4.40 (2H, m), 4.52 (2H, br), 6.53 (2H, m), 6.81 (1H, m), 7.03(1H, d), 7.97-8.21 (2H, m); MS m/z (TS⁺) 433 (MH⁺) 77 Example 40

δ_(H) (CDCl₃, 300 MHz) 1.50 (9H, br), 2.99 (3H, s), 3.29 (2H, m), 3.43(2H, m), 4.60 (2H, br), 6.81 (2H, m), 6.91 (1H, s), 7.22 (1H, d), 8.04(1H, d), 8.21 (1H, br) 78 Example 42

δ_(H) (CDCl₃, 400 MHz) 1.56 (9H, s), 2.15 (2H, m), 2.85-3.00 (7H, m),4.60 (2H, brd), 6.78 (2H, m), 6.87 (1H, s), 7.12 (1H, d), 8.03 (1H, d),8.10 (1H, s); MS m/z (TS⁺) 399 (MH⁺)

[0295]

N-Methyl-N-{2-[3-methyl-4-(methylsulfanyl)phenoxy]-5-nitrobenzyl}amineand {2-[3-methyl-4-(methylsulfanyl)phenoxy]-5-nitrophenyl}methanol.

[0296] To a suspension of the aldehyde of Preparation 39 (21.0 g, 69.2mmol) in EtOH (100 mL) was added 8M methylamine in EtOH (86.5 ml, 692mmol). A solution was given and after stirring for a short time aprecipitate was observed. This was re-dissolved by the addition of THF(100 mL), the solution was cooled to 0° C. and NaBH₄ (7.85 g, 208 mmol)was then added. The reaction was allowed to warm slowly to roomtemperature and stirred overnight before the solvent was removed invacuo. The residue was taken up in water (150 mL) and ether (150 mL),and 2M HCl was added cautiously until pH 1. The layers were separatedand the aqueous layer was washed with ether (2×100 mL). The combinedorganic extracts were dried and evaporated to give{2-[3-methyl-4-(methylsulfanyl)phenoxy]-5-nitrophenyl}methanol (18.9 g,89%) as a yellow solid; δ_(H) (CDCl₃, 400 MHz) 2.35 (3H, s), 2.48 (3H,s), 4.90 (2H, s), 6.79 (1H, d), 6.89 (1H, s), 6.91 (1H, d), 7.22 (1H,d), 8.07 (1H, dd), 8.41 (1H, d).

[0297] The aqueous layer from above was neutralised by pouring ontoexcess solid K₂CO₃. The basic solution was extracted with ether (2×100mL) and these ether extracts were dried (MgSO₄) and evaporated to giveN-methyl-N-{2-[3-methyl-4-(methylsulfanyl)phenoxy]-5-nitrobenzyl}amine(1.65 g, 7.5%) as an orange oil; MS m/z (ES⁺) 319 (MH⁺).

N-Methyl-N-{2-[3-methyl-4-(methylsulfanyl)phenoxy]-5-nitrobenzyl}aminefrom {2-[3-methyl-4-(methylsulfanyl)phenoxy]-5-nitrophenyl}methanol

[0298] Methanesulfonyl chloride (4.81 mL, 61.9 mmol) was added slowly toa solution of{2-[3-methyl-4-(methylsulfanyl)phenoxy]-5-nitrophenyl}methanol (18.9 g,61.9 mmol) and Et₃N (9.5 mL, 68.2 mmol) in DCM (60 mL). The mixture wasstirred at room temperature for 3 h then poured into water and extractedwith DCM (3 times). The combined organic extracts were dried (MgSO₄) andevaporated to give a dark, viscous oil. This oil was taken up in DCM (50mL) and 8M methylamine in EtOH (200 mL, 1.6 mol) was added followed byEt₃N (10 mL, 71.7 mmol). After stirring for 18 h the mixture wasconcentrated in vacuo to give crude amine which was used without furtherpurification.

tert-Butylmethyl{2-[3-methyl-4-(methylsulfanyl)phenoxy]-5-nitrobenzyl}carbamate

[0299] The crude amine from above was dissolved in DCM (100 mL) at 0° C.and Et₃N (11.4 mL, 81.8 mmol) was added, followed by di-teff-butyldicarbonate (15.0 g, 68.7 mmol). The reaction was allowed to warm toroom temperature and stirred for 16 h before being concentrated invacuo. The residue was partitioned between EtOAc and water and theaqueous layer was extracted with EtOAc (2 times). The combined organiclayers were dried (MgSO₄) and evaporated. The residue was purified bycolumn chromatography (SiO₂; 1^(st) column−3% MeOH in DCM; 2^(nd) columnEtOAc:pentane 1:3) to give the title compound (14.2 g, 54%) as a yellowoil; δ_(H) (CDCl₃, 400 MHz) 1.44 (9H, s), 2.32 (3H, s), 2.44 (3H, s),2.95 (3H, s), 4.56 (2H, br), 6.75 (1H, d), 6.84 (2H, m), 7.17 (1H, d),8.00 (1H, d), 8.18 (1H, br); MS m/z (TS⁺) 419 (MH⁺).

[0300] Compounds of formula XVI shown in Table 26 were preparedaccording to Example 103 from the precursors indicated TABLE 26

Preparation Precursor

data 80 Prep 77

δ_(H) (CDCl₃, 300 MHz) 1.50 (9H, br), 2.80 (3H, br), 3.20 (2H, m), 2.37(2H, m), 3.60 (2H, br), 4.40 (2H, s), 6.50-6.80 (5H, m), 7.05 (1H, d);MS m/z (ES⁺) 387 (MH⁺) 81 Prep 78

δ_(H) (CDCl₃, 400 MHz) 1.42 (9H, s), 2.05 (2H, m), 2.80 (7H, m), 4.37(2H, s), 6.50-6.65 (3H, m), 6.69 (1H, s), 6.78 (1H, d), 7.08 (1H, d); MSm/z (TS⁺) 369 (MH⁺) 82 Prep 76

δ_(H) (CDCl₃, 400 MHz) 1.43 (9H, s), 2.88 (3H, br), 3.07 (2H, m), 3.59(2H, br), 4.30 (2H, s), 4.36 (2H, m), 6.32 (1H, s), 6.40 (1H, d),6.49-6.65 (2H, m), 6.75 (1H, d), 6.88 (1H, d); MS m/z (TS⁺) 403 (MH⁺) 83Prep 79

δ_(H) (CDCl₃, 300 MHz) 1.47 (9H, s), 2.33 (3H, s), 2.40 (3H, s), 2.82(3H, br), 3.60 (2H, s), 4.35 (2H, s), 6.50-6.77 (4H, m), 6.80 (1H, d),7.16 (1H, d); MS m/z(TS⁺) 389 (MH⁺)

PREPARATION 84 tert-Butylmethyl{2-[3-methyl-4-(methylsulfanyl)phenoxy]-5-[(methylsulfonyl)amino]benzyl}carbamate

[0301]

[0302] Methanesulfonyl chloride (4.16 mL, 53.7 mmol) was added dropwiseto a solution of the aniline of Preparation 83 (9.5 g, 24.5 mmol) andEt₃N (7.5 mL, 53.8 mmol) in DCM (50 mL) at 0° C. After stirring at 0° C.for 30 min the reaction was allowed to warm to room temperature beforethe solvent was removed in vacuo. 2M NaOH (50 mL) was added to theresidue and the mixture was stirred for 30 min. The mixture wasextracted with EtOAc and the organic layer was washed with brine, dried(MgSO₄) and evaporated to give an oil. Purification by columnchromatography [SiO₂; 97.5:2.5:0.25 (DCM/MeOH/OH/880 NH₃)] gave theproduct (9.0 g, 79%) as a brown foam; δ_(H) (CDCl₃, 300 MHz) 1.43 (9H,brs), 2.35 (3H, s), 2.42 (3H, s), 2.88 (3H, brs), 3.01 (3H, s), 4.46(2H, brs), 6.76 (2H, d+s), 6.83 (1H, d), 7.16 (1H, s), 7.20 (2H, brs);MS m/z (ES⁺) 467 (MH⁺).

[0303] Compounds of formula XVII shown in Table 27 were preparedaccording to Preparation 84 from the precursors indicated. TABLE 27

Preparation Precursor

data 85 Prep 81

δ_(H) (CDCl₃, 400 MHz) (rotamers) 1.44 and 1.48 (9H, 2xs), 2.10 (2H,quintet), 2.88 (7H, m), 3.00 (3H, s), 4.49 (2H, br), 6.23 (1H, br), 6.72(1H, d), 6.81 (1H, s), 6.83 (1H, d), 7.13 (3H, m); MS m/z (TS⁺) 347 (MH⁺− Boc) 86 Prep 80

Product used without purification. 87 Prep 82

δ_(H) (CDCl₃, 400 MHz) (rotamers) 1.40 and 1.44 (9H, 2xs), 2.80 and 2.85(3H, 2xs), 2.95 (3H, s), 3.07 (2H, m), 4.38 (2H, m), 6.36 (1H, s), 6.44(1H, d), 6.84 (1H, d), 6.92 (1H, d), 7.12 (2H, m); MS m/z (TS⁺) 498(MNH₄ ⁺)

PREPARATION 88 tert-Butylmethyl{2-[3-methyl-4-(methylsulfanyl)phenoxy]-5-[methyl(methyl-sulfonyl)amino]benzyl}carbamate

[0304]

[0305] Mel (1.07 mL, 17.2 mmol) was added dropwise to a mixture of thesulfonamide of Preparation 84 (2.0 g, 4.3 mmol) and K₂CO₃ (592 mg, 4.3mmol) in CH₃CN (10 mL) under N₂. The mixture was stirred for 16 h andthen partitioned between EtOAc (50 mL) and 2M NaOH (50 mL). The organiclayer was washed with brine, dried (MgSO₄) and evaporated. The residuewas purified by column chromatography [SiO₂; 590:10:1 (DCM/MeOH/880NH₃)] to give the product (1.23 g, 60%) as a yellow oil; δ_(H) (CDCl₃,300 MHz) 1.45 (9H, s), 2.34 (3H, s), 2.42 (3H, s), 2.86 (3H, s), 2.90(3H, s), 3.28 (3H, s), 4.49 (2H, s), 6.80 (3H, br), 7.18 (3H, m); MS m/z(TS⁺) 498 (MNH₄ ⁺).

PREPARATION 89 tert-Butyl5-[(2-hydroxyethyl)(methylsulfonyl)amino]-2-[3-methyl-4-(methylsulfanyl)phenoxy]benzyl(methyl)carbamate

[0306]

[0307] 2-Bromoethanol (1.34 mL, 18.9 mmol) was added to a mixture of thesulfonamide of Preparation 84 (2.0 g, 4.3 mmol) and K₂CO₃ (2.605 g, 18.8mmol) in CH₃CN (10 mL) under N₂. The mixture was heated at reflux for 16h, cooled and then partitioned between EtOAc (50 mL) and 2M NaOH (50mL). The organic layer was washed with brine, dried (MgSO₄) andevaporated. The residue was purified by column chromatography [SiO₂;390:10:1 (DCM/MeOH/880 NH₃)] to give the product (524 mg, 24%) as a pinkfoam; δ_(H) (CDCl₃, 300 MHz) 1.42 (9H, s), 2.37 (3H, s), 2.43 (3H, s),2.91 (3H, s), 2.98 (3H, s), 3.68 (2H, brs), 3.79 (2H, d), 4.49 (2H, s),6.81 (3H, m); MS m/z (TS⁺) 528 (MNH₄ ⁺).

[0308] Fe powder (930 mg, 16.7 mmol) was added to the nitro compound ofPreparation 41 (740 mg, 2.38 mmol) in AcOH (5 mL) and water (1 mL) andthe mixture was stirred at room temperature for 16 h. The solvent wasremoved in vacuo, the residue was taken up in EtOAc (50 mL) and 10% aqK₂CO₃ (50 mL) and filtered through Arbocel®. The organic layer wasseparated and the aqueous layer was extracted with EtOAc (50 mL). Thecombined organic extracts were dried (MgSO₄) and evaporated to a brownfoam (670 mg, 99%) which was used without further purification; δ_(H)(CDCl₃, 400 MHz) 3.18 (2H, m), 4.36 (2H, m), 6.60-6.70 (2H, m),6.70-6.80 (3H, m), 6.85 (1H, s); MS m/z (TS⁺) 302 (MNH₄ ⁺).

[0309] Compounds of formula Vb, i.e. compounds of formula V where T iscyano, R⁴ is hydrogen and R⁵ is amino, shown in Table 28 were preparedaccording to Preparation 90 from the precursors indicated. TABLE 28

Preparation Precursor

data 91 Prep 35

δ_(H) (CDCl₃, 400 MHz) 2.40 (3H, s), 6.62-6.72 (2H, m), 6.80-6.90 (3H,m), 7.28 (1H, d) 92 Prep 37

δ_(H) (CDCl₃, 300 MHz) 2.47 (3H, s), 3.83 (2H, br), 6.83-6.94 (4H, m),7.01 (1H, s), 7.19 (1H, d); MS m/z(TS⁺) 308 (MNH₄ ⁺) 93 Prep 42

δ_(H) (CDCl₃, 400 MHz) 2.30 (3H, s), 2.40 (3H, s), 3.84 (2H, br), 6.77(4H, m), 6.85 (1H, s), 7.13 (3H, d); MS m/z (TS⁺) 288 (MNH₄ ⁺)

[0310]

[0311] The title compound was prepared from the nitro compound ofPreparation 43 by the method of Example 103; δ_(H) (CDCl₃, 400 MHz) 2.27(3H, s), 2.41 (3H, s), 3.66 (2H, br), 6.62 (1H, d), 6.79 (2H, s), 6.82(1H, s), 6.89 (1H, s), 7.08 (1H, d); MS m/z (ES⁺) 293 (MNa⁺), (ES⁻) 269(M−H⁺).

[0312] Compounds of formula Vc, i.e. compounds of formula V where T iscyano, R⁴ is hydrogen and Rs is —NHSO₂Me, shown in Table 29 wereprepared according to Preparation 84 from the precursors indicated.TABLE 29

Preparation Precursor

data 95 Prep 90

δ_(H) (CDCl₃, 400 MHz) 2.98 (3H, s), 3.10 (2H, m), 4.39 (2H, m), 6.67(1H, dd), 6.76 (1H, s), 6.81 (1H, d), 7.33 (1H, dd), 7.49 (1H, s); MSm/z (TS⁺) 380 (MNH₄ ⁺) 96 Prep 92

δ_(H) (CDCl₃, 300 MHz) 2.51 (3H, s), 3.06 (3H, s), 6.52 (1H, br), 6.92(1H, d), 7.02 (1H, dd), 7.14 (1H, d), 7.24 (1H, d), 7.41 (1H, dd), 7.57(1H, d); MS m/z (ES⁺) 391 (MNa⁺) 97 Prep 91

δ_(H) (CDCl₃, 400 MHz) 2.43 (3H, s), 3.02 (3h, S), 6.41 (1H, brs),6.72-6.85 (2H, m), 6.92 (1H, d), 7.28 (1H, t), 7.38 (1H, d), 7.51 (1H,s); MS m/z (ES⁺) 351 (MH⁺) 98 Prep 93

δ_(H) (CDCl₃, 400 MHz) 2.19 (3H, s), 2.42 (3H, s), 2.99 (3H, s), 6.81(1H, d), 6.86 (2H, m), 7.15 (1H, d), 7.33 (1H, d), 7.51 (1H, s); MS m/z(TS⁺) 366 (MNH₄ ⁺) 99 Prep 94

δ_(H) (CDCl₃, 400 MHz) 2.31 (3H, s), 2.43 (3H, s), 3.02 (3H, s), 6.61(1H, s), 6.72 (1H, dd), 6.83 (1H, d), 6.88 (1H, s), 7.17 (1H, d), 7.37(1H, dd), 7.55 (1H, s); MS m/z (TS⁺) 366 (MNH₄ ⁺)

PREPARATION 100N-{3-Cyano-4-[3-methyl-4-(methylsulfanyl)phenoxy]phenyl}-N-methylmethanesulfonamide

[0313]

[0314] The title compound was prepared from the sulfonamide ofPreparation 98 by the method of Preparation 88; δ_(H) (CDCl₃, 400 MHz)2.31 (3H, s), 2.44 (3H, s), 2.83 (3H, s), 3.27 (3H, s), 6.79 (1H, d),6.88 (2H, m), 7.17 (1H, d), 7.44 (1H, dd), 7.58 (1H, d); MS m/z (ES⁺)385 (MNa⁺).

[0315] (i) Preparation of [4-(allyloxy)-2-(hydroxymethyl)phenyl]methanol

[0316] Dimethyl 4-(allyloxy)phthalate [prepared according to Inouye, M.;Tsuchiya, K.; Kitao, T. Angew. Chem. 1992, 104, 198-200 (See also Angew.Chem., Int. Ed. Engl, 1992, 204-205)] (9.9 g, 38 mmol) was dissolved inTHF (40 mL) and cooled to 0° C. before the dropwise addition of lithiumaluminium hydride (1M in THF, 77 mL, 77 mmol) over 10 min. The mixturewas then allowed to stir at room temperature for 3 h before beingquenched cautiously by the addition of water (1.4 mL) followed by 2MNaOH (1.4 mL). Excess MgSO₄ was then added followed by water until agranular precipitate formed (ca. 5 mL). The mixture was then filteredand evaporated to a brown oil (7.1 g, ca. 95%). ¹H NMR showed thematerial to be of ca. 85% purity. It was used directly in the next stagewithout further purification; δ_(H) (CDCl₃, 400 MHz) 2.63 (1H, brs),2.91 (1H, brs), 4.52 (2H, m), 4.67 (4H, m), 5.26 (1H, dd), 5.38 (1H,dd), 5.97-6.09 (1H, m), 6.80 (1H, dd), 6.92 (1H, d), 7.22 (1H, d).

[0317] (ii) Preparation of 5-(allyloxy)-1,3-dihydro-2-benzothiophene

[0318] Crude diol from stage (i) (3.5 g, 18 mmol) was dissolved in DCM(60 mL) and treated with Et₃N (10 mL, 72 mmol) and the solution wascooled to 0° C. Methanesulfonyl chloride (4.2 mL, 54 mmol) was addeddropwise and the solution was stirred for 1 h being allowed to reachroom temperature. The reaction was then quenched by the addition ofwater followed by 2M HCl (50 mL). The DCM layer was separated and theaqueous layer was re-extracted with DCM (50 mL). The combined organicfractions were washed with water (50 mL), dried (MgSO₄) and concentratedto a volume of ca. 30 mL. Benzyltriethylammonium chloride (1 g) wasadded followed by a solution of sodium sulfide (5 g, 91 mmol) in water(50 mL). The mixture was stirred rapidly under a nitrogen atmosphere for15 h. The organic layer was separated and the aqueous layer wasre-extracted with DCM (50 mL). The combined organic layers were dried(MgSO₄) and evaporated to a yellow oil. Flash chromatography affordedtwo fractions; the first was pure product and the second productcontaminated with dimeric material. Trituration of the second fractioncaused crystallisation of the dimeric material which was removed byfiltration. The filtrate was combined with the first chromatographyfraction to afford the desired product (800 mg, 23%); δ_(H) (CDCl₃, 400MHz) 4.16 (2H, s), 4.19 (2H, s), 4.48 (2H, m), 5.26 (1H, d), 5.37 (1H,d), 5.95-6.06 (1H, m), 6.74 (2H, m), 7.09 (1H, d).

[0319] (iii) Preparation of 1,3-dihydro-2-benzothiophen-5-ol

[0320] The allyl ether from stage (ii) (800 mg, 4.16 mmol) was dissolvedin THF (10 mL) and treated with palladium tetrakis(triphenylphosphine)(481 mg, 0.42 mmol) followed by sodium borohydride (944 mg, 25 mmol).The mixture was then heated to 45° C. and stirred at this temperaturefor 15 h. After cooling to room temperature the THF was evaporated andthe residue partitioned between 2M NaOH solution (25 mL) and diethylether (25 mL). The aqueous layer was separated and the organic layerre-extracted with 2M NaOH solution (25 mL). The combined aqueous layerswere neutralised to pH 7-8 with concentrated hydrochloric acid andextracted with EtOAc (2×25 mL). The combined organic extracts were dried(MgSO₄) and evaporated to a clear oil of the title phenol whichsolidified upon standing (540 mg, 85%); 4.14 (2H, s), 4.17 (2H, s),6.63-6.68 (2H, m), 7.04 (1H, d).

[0321] Biological Activity

[0322] A number of compounds were tested for biological activity bytheir ability to inhibit the uptake of serotonin by human serotonintransporters as follows.

[0323] (i) Cell Culture

[0324] Human embryonic kidney cells (HEK-293) stably transfected witheither the human serotonin transporter (hSERT), noradrenalinetransporter (hNET) or dopamine transporter (hDAT) were cultured understandard cell culture techniques (cells were grown at 37° C. and 5% CO₂in DMEM-culture media (supplemented with 10% dialysed foetal calf serum(FCS), 2mM l-glutamine and 250 μg/ml geneticin)). Cells were harvestedfor the assay to yield a cell suspension of 750,000 cells/ml.

[0325] (i) Determination of Inhibitor Potency

[0326] All test compounds were dissolved in 100% DMSO and diluted downin assay buffer to give appropriate test concentrations. Assays werecarried out in 96-well filter bottom plates. Cells (7500 cells/assaywell) were pre-incubated in standard assay buffer containing either testcompound, standard inhibitor or compound vehicle (1% DMSO) for 5minutes. Reactions were started by addition of either ³H-Serotonin,³H-Noradrenaline or ³H-Dopamine substrates. All reactions were carriedout at room temperature in a shaking incubator. Incubation times were 5minutes for the hSERT and hDAT assays and 15 minutes for the hNET assay.Reactions were terminated by removal of the reaction mixture using avacuum manifold followed by rapid washing with ice cold assay buffer.The quantity of ³H-substrate incorporated into the cells was thenquantified.

[0327] Assay plates were dried in a microwave oven, scintillation fluidadded, and radioactivity measured. Potency of test compounds wasquantified as IC₅₀ values (concentration of test compound required toinhibit the specific uptake of radiolabelled substrate into the cells by50%).

[0328] (iii) Standard Assay Buffer Composition

[0329] Trizma hydrochloride (26 mM)

[0330] NaCl (124 mM)

[0331] KCl (4.5 mM)

[0332] KH₂PO₄ (1.2 mM)

[0333] MgCl₂.6H₂O (1.3 mM)

[0334] Ascorbic acid (1.136 mM)

[0335] Glucose (5.55 mM)

[0336] pH 7.40

[0337] CaCl₂ (2.8 mM)

[0338] Pargyline (100 μM)

[0339] Note: The pH of the buffer was adjusted to 7.40 with 1M NaOHbefore addition of CaCl₂ and pargyline. Summary of Assay ParametershSERT hDAT hNET Assay Assay Assay Cell concentration per 75,000 75,00075,000 assay well. Substrate Concentration. ³H-5HT ³H-Dopamine³H-Noradrenaline (50 nM) (200 nM) (200 nM) Incubation time (minutes) 5 515

[0340] Compounds having a serotonin re-uptake inhibition (SRI) IC₅₀value of less than or equal to 100 nM include the title compounds ofExamples 1-6, 8-23, 25, 26, 29-32, 34-36, 43, 45-49, 51, 56-102,109-130.

[0341] Compounds having an serotonin re-uptake inhibition (SRI) IC₅₀value of less than or equal to 100 nM and which are more than 10-fold aspotent in the inhibition of serotonin re-uptake than in the inhibitionof dopamine re-uptake or noradrenaline re-uptake include the titlecompounds of Examples 1-6, 9-13, 16-19, 21, 22, 25, 26, 29-32, 34-36,43, 45, 47-49, 51, 57-88, 90-102, 109-121, 123, 124, 127, 129.

[0342] Compounds having an serotonin re-uptake inhibition (SRI) IC₅₀value of less than or equal to 100 nM and which are more than 100-foldas potent in the inhibition of serotonin re-uptake than in theinhibition of dopamine re-uptake or noradrenaline re-uptake include thetitle compounds of Examples 1, 2, 4, 5, 9, 12, 13, 16-19, 21, 22, 25,26, 29-32, 34-36, 43, 45, 48, 49, 58-80, 83-88, 90, 92-97, 99-102,111-113, 115-118, 120, 123, 124, 127.

[0343] Compounds having an serotonin re-uptake inhibition (SRI) IC₅₀value of less than or equal to 50 nM and which are more than 100-fold aspotent in the inhibition of serotonin re-uptake than in the inhibitionof dopamine re-uptake and noradrenaline re-uptake include the titlecompounds of Examples 1, 2, 4, 9, 12, 17, 18, 26, 29, 30, 36, 43, 45,48, 49, 60-66, 68-75, 78, 79, 90, 92-94, 100, 102, 116, 118, 124.

[0344] In particular, the title compound of Example 16 had a serotoninre-uptake inhibition (SRI) IC₅₀ of 4.7 nM; the title compound of Example29 had a serotonin re-uptake inhibition (SRI) IC₅₀ of 2.0 nM; and thetitle compound of Example 62 had a serotonin re-uptake inhibition (SRI)IC₅₀ of 3.7 nM.

1. A compound of general formula (I), pharmaceutically acceptable salts,solvates or polymorphs thereof;

wherein; R¹ and R², which may be the same or different, are H,C₁-C₆alkyl or (CH₂)_(d)(C₃-C₆cycloalkyl) wherein d=0, 1, 2 or 3; or R¹and R² together with the nitrogen to which they are attached form anazetidine ring; Z or Y is —SR³ and the other Z or Y is halogen or —R³;wherein R³ is independently C₁-C₄ alkyl optionally substituted withfluorine; except that R³ is not CF₃; or Z and Y are linked so that,together with the interconnecting atoms, Z and Y form a fused 5 to7-membered carbocyclic or heterocyclic ring which may be saturated,unsaturated or aromatic, and wherein when Z and Y form a heterocyclicring, in addition to carbon atoms, the linkage contains one or twoheteroatoms independently selected from oxygen, sulfur and nitrogen;with the proviso that when R⁵ is fluorine and R² is methyl then thefused ring is not 1,3-dioxalane and Z and Y together do not form a fusedphenyl ring; R⁴ and R⁵, which may be the same or different, are: A—X,wherein A═—CH═CH— or —(CH₂)_(p)— where p is 0, 1 or 2; X is hydrogen, F,Cl, Br, I, CONR⁶R⁷, SO₂NR⁶R⁷, SO₂NHC(═O)R⁶, OH, C₁₋₄alkoxy, NR⁸SO₂R⁹,NO₂, NR⁶R¹¹, CN, CO₂R¹⁰, CHO, SR¹⁰, S(O)R⁹ or SO₂R¹⁰; R⁶, R⁷, R⁸ and R¹⁰which may be the same or different, are hydrogen or C₁₋₆alkyl optionallysubstituted independently by one or more R¹²; R⁹ is C₁₋₆ alkyloptionally substituted independently by one or more R¹²; R¹¹ ishydrogen, C₁₋₆ alkyl optionally substituted independently by one or moreR¹², C(O)R⁶, CO₂R⁹, C(O)NHR⁶ or SO₂NR⁶R⁷; R¹² is F, OH, CO₂H,C₃₋₆cycloalkyl, NH₂, CONH₂, C₁₋₆alkoxy, C₁₋₆alkoxycarbonyl or a 5- or6-membered heterocyclic ring containing 1, 2 or 3 heteroatoms selectedfrom N, S and O optionally substituted independently by one or more R¹³;or R⁶ and R⁷, together with the nitrogen to which they are attached,form a 4-, 5- or 6-membered heterocyclic ring optionally substitutedindependently by one or more R¹³; or a 5- or 6-membered heterocyclicring containing 1, 2 or 3 heteroatoms selected from N, S and O,optionally substituted independently by one or more R¹³; wherein R¹³ ishydroxy, C₁-C₄alkoxy, F, C₁-C₆alkyl, haloalkyl, haloalkoxy, —NH₂,—NH(C₁-C₆alkyl) or —N(C₁-C₆alkyl)₂.
 2. A compound according to claim 1,pharmaceutically acceptable salts, solvates or polymorphs thereof,wherein R¹ and R², which may be the same or different, are hydrogen orC₁-C₆alkyl.
 3. A compound according to claim 2, pharmaceuticallyacceptable salts, solvates or polymorphs thereof, wherein R¹ and R²,which may be the same or different, are hydrogen or methyl.
 4. Acompound according to claims 1 or 2, pharmaceutically acceptable salts,solvates or polymorphs thereof, wherein when Z or Y is —SR³, R³ ismethyl or ethyl.
 5. A compound according to claims 1 or 2,pharmaceutically acceptable salts, solvates or polymorphs thereof,wherein when Z and Y are linked to form a fused ring, the ring is aheterocyclic ring.
 6. A compound according to claim 4, pharmaceuticallyacceptable salts, solvates or polymorphs thereof, wherein in addition tocarbon atoms, the linkage contains one or two sulfur atoms.
 7. Acompound according to claim 1, pharmaceutically acceptable salts,solvates or polymorphs thereof, wherein R⁶ and R⁷, which may be the sameor different, are hydrogen, C₁-C₃alkyl optionally substituted byhydroxy, —CONH₂ or C₁-C₃alkoxy.
 8. A compound according to claim 1,pharmaceutically acceptable salts, solvates or polymorphs thereof,wherein R⁸ is hydrogen, hydroxyethyl or methyl.
 9. A compound accordingto claim 1, pharmaceutically acceptable salts, solvates or polymorphsthereof, wherein R⁹ is methyl, ethyl, isopropyl, trifluoromethyl ormethoxyethyl.
 10. A compound according to claim 1, pharmaceuticallyacceptable salts, solvates or polymorphs thereof, wherein p is 1 or 0.11. A compound according to claim 1, pharmaceutically acceptable salts,solvates or polymorphs thereof, wherein R⁴ and R⁵, which may be the sameor different, are —(CH₂)_(p)—X, where p is 0, 1 or 2; X is hydrogen,hydroxy, CONR⁶R⁷, SO₂NR⁶R⁷, NR⁸SO₂R⁹, SR¹⁰, SOR⁹ or SO₂R¹⁰ wherein R⁶,R⁷, R⁸, R⁹ and R¹⁰ are as defined in claim 1, or a 5- or 6-memberedheterocyclic ring containing 1, 2 or 3 heteroatoms selected from N, Sand O.
 12. A compound according to claim 1, pharmaceutically acceptablesalts, solvates or polymorphs thereof, wherein R⁴ and R⁵, which may bethe same or different, are: —(CH₂)_(p)—X, where p is 0 or 1; X ishydrogen, hydroxy, CONR⁶R⁷, SO₂NR⁶R⁷ or NR⁸SO₂R⁹; wherein R⁶ and R⁷,which may be the same or different, are hydrogen or C₁-C₃alkyloptionally substituted by hydroxy, —CONH₂ or C₁-C₃alkoxy (preferablymethoxy); R⁸ is hydrogen, hydroxyethyl or methyl; or R⁹ is methyl,ethyl, isopropyl, trifluoromethyl or methoxyethyl; or triazolyl,imidazolyl or pyrazolyl.
 13. A compound according to claim 1,pharmaceutically acceptable salts, solvates or polymorphs thereof,wherein R⁴ and R⁵ are not both hydrogen.
 14. A compound according toclaim 1, pharmaceutically acceptable salts, solvates or polymorphsthereof, wherein at least one of R⁴ and R⁵ is A—X, wherein X is NR⁶R¹¹,R¹¹ is hydrogen or C₁₋₆ alkyl and A and R⁶ are as defined in claim 1.15. A compound according to claim 1, pharmaceutically acceptable salts,solvates or polymorphs thereof, wherein R⁴ is hydrogen.
 16. A compoundaccording to claim 1, pharmaceutically acceptable salts, solvates orpolymorphs thereof, wherein R⁶ and R⁷, which may be the same ordifferent, are hydrogen, C₁-C₃alkyl optionally substituted by hydroxy,—CONH₂ or C₁-C₃alkoxy (preferably methoxy).
 17. A compound according toclaim 16, pharmaceutically acceptable salts, solvates or polymorphsthereof, wherein R⁶ and R⁷, which may be the same or different, arehydrogen or methyl.
 18. A compound according to claim 16,pharmaceutically acceptable salts, solvates or polymorphs thereof,wherein R⁶ and R⁷ are hydrogen.
 19. A compound according to claim 1,pharmaceutically acceptable salts, solvates or polymorphs thereof,wherein R⁶ and R⁷, together with the nitrogen to which they areattached, form a heterocyclic ring, selected from a pyrrolidine ringoptionally substituted with OH or CONH₂, a piperidine ring optionallysubstituted with OH or CONH₂ and a morpholine ring optionallysubstituted with CONH₂.
 20. A compound according to claim 1,pharmaceutically acceptable salts, solvates or polymorphs thereof,wherein at least one of R⁴ and R⁵ is A—X, wherein X is CO₂R¹⁰, SR¹⁰ orSO₂R¹⁰, R¹⁰ is independently for each occurrence methyl or ethyl and Ais as defined in claim
 1. 21. A compound according to claim 1,pharmaceutically acceptable salts, solvates or polymorphs thereof,wherein R¹ and R², which may be the same or different, are hydrogen ormethyl, Z or Y is —SR³ and the other Z or Y is halogen or —R³, whereinR³ is methyl or ethyl or Z and Y are linked together with theinterconnecting atoms thereof to form a fused 5 to 7-memberedcarbocyclic or heterocyclic ring which may be saturated, unsaturated oraromatic, and wherein when Z and Y form a heterocyclic ring, said ringcontains one or two heteroatoms independently selected from oxygen,sulfur and nitrogen; and R⁴ and R⁵, which may be the same or different,are (CH₂)_(p)—X or an oxadiazolyl, triazolyl, imidazolyl, oxazolyl,pyrazolyl, pyridinyl or pyrimidinyl group, wherein: p is 0 or 1; X ishydrogen, hydroxy, CONR⁶R⁷, SO₂NR⁶R⁷, NR⁸SO₂R⁹, SR¹⁰, SOR⁹ or SO₂R¹⁰ andwherein R⁶ and R⁷, which may be the same or different, are hydrogen,C₁-C₃alkyl optionally substituted by hydroxy, —CONH₂ or C₁-C₃alkoxy(preferably methoxy); or R⁶ and R⁷, together with the nitrogen to whichthey are attached, form a morpholine, pyrrolidine or piperidine ringeach of which may be substituted by OH or CONH₂; R⁸ is hydrogen,hydroxyethyl or methyl; R⁹ is methyl, ethyl, isopropyl, trifluoromethylor methoxyethyl; and R¹⁰ is methyl or ethyl.
 22. A compound according toclaim 20, pharmaceutically acceptable salts, solvates or polymorphsthereof, wherein Z or Y is —SR³ and the other Z or Y is halogen or —R³,wherein R³is methyl or ethyl or Z and Y are linked together with theinterconnecting atoms thereof to form a hetrocyclic ring containing 1 or2 sulfur atorms; and R⁴ and R⁵, which may be the same or different, are—(CH₂)_(p)—X, triazolyl, imidazolyl or pyrazolyl, wherein: p is 0 or 1;X is hydrogen, hydroxy, CONR⁶R⁷, SO₂NR⁶R⁷ or NR⁸SO₂R⁹; wherein R⁶ andR⁷, which may be the same or different, are hydrogen, C₁-C₃alkyloptionally substituted by hydroxy, —CONH₂ or C₁-C₃alkoxy; R⁸ ishydrogen, hydroxyethyl or methyl; R⁹ is methyl, ethyl, isopropyl,trifluoromethyl or methoxyethyl.
 23. A compound according to claim 21,pharmaceutically acceptable salts, solvates or polymorphs thereof,wherein R⁴ is hydrogen.
 24. A compound according to claim 22,pharmaceutically acceptable salts, solvates or polymorphs thereof, withthe proviso that R⁴ and R⁵ are not both hydrogen.
 25. A compoundaccording to claim 1, pharmaceutically acceptable salts, solvates orpolymorphs thereof, selected from the group:4-(2,3-dihydro-1-benzothien-5-yloxy)-3-[(methylamino)methyl]-benzenesulfonamide;3-[(dimethylamino)methyl]-4-[3-methyl-4-(methylsulfanyl)phenoxy]-benzenesulfonamide;4-(2,3-dihydro-1-benzothien-5-yloxy)-3-[(dimethylamino)methyl]-benzenesulfonamide;4-[3-chloro-4-(methylsulfanyl)phenoxy]-3-[(dimethylamino)methyl]-benzenesulfonamide;3-[(dimethylamino)methyl]-4-[3-fluoro-4-(methylsulfanyl)phenoxy]-benzenesulfonamide;N,N-dimethyl-N-[2-(6-quinolinyloxy)benzyl]amine;3-[(methylamino)methyl]-4-(6-quinolinyloxy)benzenesulfonamide;4-(2,3-dihydro-1-benzothien-5-yloxy)-3-[(methylamino)methyl]benzamide;4-(2,3-dihydro-1-benzothien-5-yloxy)-N-methyl-3-[(methylamino)methyl]-benzamide;N-{3-[(methylamino)methyl]4-[3-methyl-4-(methylsulfanyl)phenoxy]benzyl}methanesulfonamide;3-[(methylamino)methyl]-4-[3-methyl-4-(methylsulfanyl)phenoxy]benzamide;4-(2,3-dihydro-1,4-benzoxathiin-7-yloxy)-3-[(dimethylamino)methyl]benzamide;{3-[(dimethylamino)methyl]-4-[3-fluoro-4-(methylsulfanyl)phenoxy]phenyl}-methanol;3-[(dimethylamino)methyl]-4-(6-quinolinyloxy)benzamide;3-[(methylamino)methyl]-4-(6-quinolinyloxy)benzamide;N-methyl-N-{3-[(methylamino)methyl]-4-[3-methyl-4-(methylsulfanyl)phenoxy]-phenyl}methanesulfonamideandN-{4-(2,3-dihydro-1,4-benzoxathiin-7-yloxy)-3-[(dimethylamino)methyl]phenyl}-methanesulfonamide.26. A pharmaceutical formulation comprising a compound as defined inclaim 1, or pharmaceutically acceptable salts, solvates or polymorphsthereof, and a pharmaceutically acceptable adjuvant, diluent or carrier.27. A method of treatment or prevention of a disorder in which theregulation of monoamine transporter function is implicated, comprisingthe administration of an effective amount of a compound as defined inclaim 1, pharmaceutically acceptable salts, solvates or polymorphsthereof, to a patient in need of such treatment or prevention.
 28. Amethod of treatment or prevention of premature ejaculation, comprisingthe administration of an effective amount of a compound as defined inclaim 1, pharmaceutically acceptable salts, solvates or polymorphsthereof, to a patient in need of such treatment or prevention.
 29. Amethod of increasing ejaculatory latency which comprises theadministration of an effective amount of a compound as defined in claim1, pharmaceutically acceptable salts, solvates or polymorphs thereof, toa male desiring increased ejaculatory latency.
 30. A process for thepreparation of a compound of general formula (I);

wherein R¹, R², R⁴, R⁵, X and Z are as defined in claim 1 comprisingreacting a compound of general formula Ia

under suitable reaction conditions to form the compound of formula I,wherein the suitable reaction conditions are: i) where R⁴/R⁵ arehalogen, by reaction of (Ia) with a suitable halogenating agent in aninert solvent which does not adversely affect the reaction; ii) whereR⁴/R⁵ are —NO₂, by reaction of (Ia) with a suitable nitrating agent inan inert solvent which does not adversely affect the reaction at, orbelow, room temperature; or ii) where R⁴/R⁵ is —SO₂NR⁶R⁷ by reaction ofan intermediate sulfonyl chloride with the requisite amine of formulaHNR⁶R⁷ in a suitable solvent.
 31. A process according to claim 30 forpreparing a compound of formula (Iq),

comprising a) reacting a compound of formula Ia, optionally in asuitable solvent, with chlorosulfonic acid to give a compound of formulaXVIII

followed by b) reacting with HNR⁶R⁷ to give the compound of formula(Iq).
 32. A process according to claim 31 wherein the compound offormula XVIII is generated in situ and reacted with HNR⁶R⁷ withoutisolation.
 33. A process according to claim 30, 31 or 32 which furthercomprises the step of preparing compounds of formula (Ia), by reactingcompounds of formula (IIa)

with a compound of formula HNR¹R², or with a suitable salt form thereof,together with a hydride reducing agent in a suitable solvent, to formthe compound of formula (Ia).
 34. An intermediate compound of formula(XVIII) as defined in claims 31 or
 32. 35. An intermediate compound offormula (IIa) as defined in claim
 33. 36. A process for preparing acompound of formula I

wherein R¹, R², R⁴, R⁵, X and Z are as defined in claim 1, comprisingreacting a compound of formula II

with a compound of formula HNR¹R² or with a suitable salt form thereof,together with a hydride reducing agent in a suitable solvent.
 37. Aprocess according to claim 36 which further comprises coupling undersuitable reaction conditions a compound of formula III,

wherein L is a suitable leaving group such as halogen or a sulfonateester such as trifluoromethanesulfonate or methanesulfonate, with acompound of formula IV

to give the compound of formula II.
 38. An intermediate compound offormula II as defined in claim
 36. 39. A compound of general formula(I), or pharmaceutically acceptable salts, solvates or polymorphsthereof, wherein R¹, R², Y and Z are as defined in claim 1; and R⁴ andR⁵, which may be the same or different, are —(CH₂)_(p)—A′, wherein p is0, 1 or 2 and A′ is a polar group.
 40. A compound according to claim 39,wherein the polar group has a δ-value more negative than −0.1.